Editorial

4 pages, 200 KiB

Open AccessEditorial

Kidney Inflammation, Injury and Regeneration

by Patrick C. Baer, Benjamin Koch and Helmut Geiger

Int. J. Mol. Sci. 2020, 21(3), 1164; https://doi.org/10.3390/ijms21031164 - 10 Feb 2020

Cited by 9 | Viewed by 2695

Damage to kidney cells can occur due to a variety of ischemic and toxic insults and leads to inflammation and cell death, which can result in acute kidney injury (AKI) [...] Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

Research

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15 pages, 3223 KiB

Open AccessArticle

No Cytotoxic and Inflammatory Effects of Empagliflozin and Dapagliflozin on Primary Renal Proximal Tubular Epithelial Cells under Diabetic Conditions In Vitro

by Patrick C. Baer, Benjamin Koch, Janina Freitag, Ralf Schubert and Helmut Geiger

Int. J. Mol. Sci. 2020, 21(2), 391; https://doi.org/10.3390/ijms21020391 - 08 Jan 2020

Cited by 10 | Viewed by 4082

Abstract

Gliflozins are inhibitors of the renal proximal tubular sodium-glucose co-transporter-2 (SGLT-2), that inhibit reabsorption of urinary glucose and they are able to reduce hyperglycemia in patients with type 2 diabetes. A renoprotective function of gliflozins has been proven in diabetic nephropathy, but harmful [...] Read more.

Gliflozins are inhibitors of the renal proximal tubular sodium-glucose co-transporter-2 (SGLT-2), that inhibit reabsorption of urinary glucose and they are able to reduce hyperglycemia in patients with type 2 diabetes. A renoprotective function of gliflozins has been proven in diabetic nephropathy, but harmful side effects on the kidney have also been described. In the current project, primary highly purified human renal proximal tubular epithelial cells (PTCs) have been shown to express functional SGLT-2, and were used as an in vitro model to study possible cellular damage induced by two therapeutically used gliflozins: empagliflozin and dapagliflozin. Cell viability, proliferation, and cytotoxicity assays revealed that neither empagliflozin nor dapagliflozin induce effects in PTCs cultured in a hyperglycemic environment, or in co-medication with ramipril or hydro-chloro-thiazide. Oxidative stress was significantly lowered by dapagliflozin but not by empagliflozin. No effect of either inhibitor could be detected on mRNA and protein expression of the pro-inflammatory cytokine interleukin-6 and the renal injury markers KIM-1 and NGAL. In conclusion, empa- and dapagliflozin in therapeutic concentrations were shown to induce no direct cell injury in cultured primary renal PTCs in hyperglycemic conditions. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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14 pages, 4509 KiB

Open AccessArticle

Effects of Farnesiferol B on Ischemia-Reperfusion-Induced Renal Damage, Inflammation, and NF-κB Signaling

by Lu Zhang, Xianjun Fu, Ting Gui, Tianqi Wang, Zhenguo Wang, Gerd A. Kullak-Ublick and Zhibo Gai

Int. J. Mol. Sci. 2019, 20(24), 6280; https://doi.org/10.3390/ijms20246280 - 12 Dec 2019

Cited by 14 | Viewed by 3385

Abstract

Background: G-protein-coupled bile acid receptor (TGR5), a membrane bile acid receptor, regulates macrophage reactivity, and attenuates inflammation in different disease models. However, the regulatory effects of TGR5 in ischemia/reperfusion (I/R)-induced kidney injury and inflammation have not yet been extensively studied. Therefore, we hypothesize [...] Read more.

Background: G-protein-coupled bile acid receptor (TGR5), a membrane bile acid receptor, regulates macrophage reactivity, and attenuates inflammation in different disease models. However, the regulatory effects of TGR5 in ischemia/reperfusion (I/R)-induced kidney injury and inflammation have not yet been extensively studied. Therefore, we hypothesize that Farnesiferol B, a natural TGR5 agonist, could alleviate renal I/R injury by reducing inflammation and macrophage migration through activating TGR5. Methods: Mice were treated with Farnesiferol B before I/R or sham procedures. Renal function, pathological analysis, and inflammatory mediators were examined. In vitro, the regulatory effects of Farnesiferol B on the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway in macrophages were investigated. Results: After I/R, Farnesiferol B-treated mice displayed better renal function and less tubular damage. Farnesiferol B reduced renal oxidative stress and inflammation significantly. In vitro, Farnesiferol B treatment alleviated lipopolysaccharide (LPS)-induced macrophage migration and activation, as well as LPS-induced NF-κB activation through TGR5. Conclusions: Farnesiferol B could protect kidney function from I/R-induced damage by attenuating inflammation though activating TGR5 in macrophages. Farnesiferol B might be a potent TGR5 ligand for the treatment of I/R-induced renal inflammation. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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16 pages, 2627 KiB

Open AccessArticle

Renal Chemerin Expression is Induced in Models of Hypertensive Nephropathy and Glomerulonephritis and Correlates with Markers of Inflammation and Fibrosis

by Alexander Mocker, Karl F. Hilgers, Nada Cordasic, Rainer Wachtveitl, Carlos Menendez-Castro, Joachim Woelfle, Andrea Hartner and Fabian B. Fahlbusch

Int. J. Mol. Sci. 2019, 20(24), 6240; https://doi.org/10.3390/ijms20246240 - 11 Dec 2019

Cited by 17 | Viewed by 3472

Abstract

Chemerin and its receptor, chemokine-like receptor 1 (CmklR1), are associated with chemotaxis, inflammation, and endothelial function, especially in metabolic syndrome, coronary heart disease, and hypertension. In humans, circulating chemerin levels and renal function show an inverse relation. So far, little is known about [...] Read more.

Chemerin and its receptor, chemokine-like receptor 1 (CmklR1), are associated with chemotaxis, inflammation, and endothelial function, especially in metabolic syndrome, coronary heart disease, and hypertension. In humans, circulating chemerin levels and renal function show an inverse relation. So far, little is known about the potential role of chemerin in hypertensive nephropathy and renal inflammation. Therefore, we determined systemic and renal chemerin levels in 2-kidney-1-clip (2k1c) hypertensive and Thy1.1 nephritic rats, respectively, to explore the correlation between chemerin and markers of renal inflammation and fibrosis. Immunohistochemistry revealed a model-specific induction of chemerin expression at the corresponding site of renal damage (tubular vs. glomerular). In both models, renal expression of chemerin (RT-PCR, Western blot) was increased and correlated positively with markers of inflammation and fibrosis. In contrast, circulating chemerin levels remained unchanged. Taken together, these findings demonstrate that renal chemerin expression is associated with processes of inflammation and fibrosis-related to renal damage. However, its use as circulating biomarker of renal inflammation seems to be limited in our rat models. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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12 pages, 2373 KiB

Open AccessArticle

Xanthine Oxidase Inhibitor Febuxostat Exerts an Anti-Inflammatory Action and Protects against Diabetic Nephropathy Development in KK-Ay Obese Diabetic Mice

by Yu Mizuno, Takeshi Yamamotoya, Yusuke Nakatsu, Koji Ueda, Yasuka Matsunaga, Masa-Ki Inoue, Hideyuki Sakoda, Midori Fujishiro, Hiraku Ono, Takako Kikuchi, Masahiro Takahashi, Kenichi Morii, Kensuke Sasaki, Takao Masaki, Tomoichiro Asano and Akifumi Kushiyama

Int. J. Mol. Sci. 2019, 20(19), 4680; https://doi.org/10.3390/ijms20194680 - 21 Sep 2019

Cited by 28 | Viewed by 5528

Abstract

Hyperuricemia has been recognized as a risk factor for insulin resistance as well as one of the factors leading to diabetic kidney disease (DKD). Since DKD is the most common cause of end-stage renal disease, we investigated whether febuxostat, a xanthine oxidase (XO) [...] Read more.

Hyperuricemia has been recognized as a risk factor for insulin resistance as well as one of the factors leading to diabetic kidney disease (DKD). Since DKD is the most common cause of end-stage renal disease, we investigated whether febuxostat, a xanthine oxidase (XO) inhibitor, exerts a protective effect against the development of DKD. We used KK-Ay mice, an established obese diabetic rodent model. Eight-week-old KK-Ay mice were provided drinking water with or without febuxostat (15 μg/mL) for 12 weeks and then subjected to experimentation. Urine albumin secretion and degrees of glomerular injury judged by microscopic observations were markedly higher in KK-Ay than in control lean mice. These elevations were significantly normalized by febuxostat treatment. On the other hand, body weights and high serum glucose concentrations and glycated albumin levels of KK-Ay mice were not affected by febuxostat treatment, despite glucose tolerance and insulin tolerance tests having revealed febuxostat significantly improved insulin sensitivity and glucose tolerance. Interestingly, the IL-1β, IL-6, MCP-1, and ICAM-1 mRNA levels, which were increased in KK-Ay mouse kidneys as compared with normal controls, were suppressed by febuxostat administration. These data indicate a protective effect of XO inhibitors against the development of DKD, and the underlying mechanism likely involves inflammation suppression which is independent of hyperglycemia amelioration. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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10 pages, 1765 KiB

Open AccessCommunication

Noninvasive Urinary Monitoring of Progression in IgA Nephropathy

by Joshua Y. C. Yang, Reuben D. Sarwal, Fernando C. Fervenza, Minnie M. Sarwal and Richard A. Lafayette

Int. J. Mol. Sci. 2019, 20(18), 4463; https://doi.org/10.3390/ijms20184463 - 10 Sep 2019

Cited by 9 | Viewed by 3642

Abstract

Standard methods for detecting and monitoring of IgA nephropathy (IgAN) have conventionally required kidney biopsies or suffer from poor sensitivity and specificity. The Kidney Injury Test (KIT) Assay of urinary biomarkers has previously been shown to distinguish between various kidney pathologies, including chronic [...] Read more.

Standard methods for detecting and monitoring of IgA nephropathy (IgAN) have conventionally required kidney biopsies or suffer from poor sensitivity and specificity. The Kidney Injury Test (KIT) Assay of urinary biomarkers has previously been shown to distinguish between various kidney pathologies, including chronic kidney disease, nephrolithiasis, and transplant rejection. This validation study uses the KIT Assay to investigate the clinical utility of the non-invasive detection of IgAN and predicting the progression of renal damage over time. The study design benefits from longitudinally collected urine samples from an investigator-initiated, multicenter, prospective study, evaluating the efficacy of corticosteroids versus Rituximab for preventing progressive IgAN. A total of 131 urine samples were processed for this study; 64 urine samples were collected from 34 IgAN patients, and urine samples from 64 demographically matched healthy controls were also collected; multiple urinary biomarkers consisting of cell-free DNA, methylated cell-free DNA, DMAIMO, MAMIMO, total protein, clusterin, creatinine, and CXCL10 were measured by the microwell-based KIT Assay. An IgA risk score (KIT-IgA) was significantly higher in IgAN patients as compared to healthy control (87.76 vs. 14.03, p < 0.0001) and performed better than proteinuria in discriminating between the two groups. The KIT Assay biomarkers, measured on a spot random urine sample at study entry could distinguish patients likely to have progressive renal dysfunction a year later. These data support the pursuit of larger prospective studies to evaluate the predictive performance of the KIT-IgA score in both screening for non-invasive diagnosis of IgAN, and for predicting risk of progressive renal disease from IgA and utilizing the KIT score for potentially evaluating the efficacy of IgAN-targeted therapies. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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13 pages, 5198 KiB

Open AccessArticle

Targeting ROS and cPLA2/COX2 Expressions Ameliorated Renal Damage in Obese Mice with Endotoxemia

by Jia-Feng Chang, Jih-Chen Yeh, Chun-Ta Ho, Shih-Hao Liu, Chih-Yu Hsieh, Ting-Ming Wang, Shu-Wei Chang, I-Ta Lee, Kuo-Yang Huang, Jen-Yu Wang and Wei-Ning Lin

Int. J. Mol. Sci. 2019, 20(18), 4393; https://doi.org/10.3390/ijms20184393 - 06 Sep 2019

Cited by 18 | Viewed by 4072

Abstract

Obesity is associated with metabolic endotoxemia, reactive oxygen species (ROS), chronic inflammation, and obese kidney fibrosis. Although the fat–intestine–kidney axis has been documented, the pathomechanism and therapeutic targets of obese kidney fibrosis remain unelucidated. To mimic obese humans with metabolic endotoxemia, high-fat-diet-fed mice [...] Read more.

Obesity is associated with metabolic endotoxemia, reactive oxygen species (ROS), chronic inflammation, and obese kidney fibrosis. Although the fat–intestine–kidney axis has been documented, the pathomechanism and therapeutic targets of obese kidney fibrosis remain unelucidated. To mimic obese humans with metabolic endotoxemia, high-fat-diet-fed mice (HF group) were injected with lipopolysaccharide (LPS) to yield the obese kidney fibrosis–metabolic endotoxemia mouse model (HL group). Therapeutic effects of ROS, cytosolic phospholipases A2 (cPLA2) and cyclooxygenase-2 (COX-2) inhibitors were analyzed with a quantitative comparison of immunohistochemistry stains and morphometric approach in the tubulointerstitium of different groups. Compared with basal and HF groups, the HL group exhibited the most prominent obese kidney fibrosis, tubular epithelial lipid vacuoles, and lymphocyte infiltration in the tubulointerstitium. Furthermore, inhibitors of nonspecific ROS, cPLA2 and COX-2 ameliorated the above renal damages. Notably, the ROS-inhibitor-treated group ameliorated not only oxidative injury but also the expression of cPLA2 and COX-2, indicating that ROS functions as the upstream signaling molecule in the inflammatory cascade of obese kidney fibrosis. ROS acts as a key messenger in the signaling transduction of obese kidney fibrosis, activating downstream cPLA2 and COX-2. The given antioxidant treatment ameliorates obese kidney fibrosis resulting from a combined high-fat diet and LPS—ROS could serve as a potential therapeutic target of obese kidney fibrosis with metabolic endotoxemia. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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19 pages, 6261 KiB

Open AccessArticle

LPS-Binding Protein Modulates Acute Renal Fibrosis by Inducing Pericyte-to-Myofibroblast Trans-Differentiation through TLR-4 Signaling

by Giuseppe Castellano, Alessandra Stasi, Rossana Franzin, Fabio Sallustio, Chiara Divella, Alessandra Spinelli, Giuseppe Stefano Netti, Enrico Fiaccadori, Vincenzo Cantaluppi, Antonio Crovace, Francesco Staffieri, Luca Lacitignola, Giuseppe Grandaliano, Simona Simone, Giovanni Battista Pertosa and Loreto Gesualdo

Int. J. Mol. Sci. 2019, 20(15), 3682; https://doi.org/10.3390/ijms20153682 - 27 Jul 2019

Cited by 33 | Viewed by 4288

Abstract

During sepsis, the increased synthesis of circulating lipopolysaccharide (LPS)-binding protein (LBP) activates LPS/TLR4 signaling in renal resident cells, leading to acute kidney injury (AKI). Pericytes are the major source of myofibroblasts during chronic kidney disease (CKD), but their involvement in AKI is poorly [...] Read more.

During sepsis, the increased synthesis of circulating lipopolysaccharide (LPS)-binding protein (LBP) activates LPS/TLR4 signaling in renal resident cells, leading to acute kidney injury (AKI). Pericytes are the major source of myofibroblasts during chronic kidney disease (CKD), but their involvement in AKI is poorly understood. Here, we investigate the occurrence of pericyte-to-myofibroblast trans-differentiation (PMT) in sepsis-induced AKI. In a swine model of sepsis-induced AKI, PMT was detected within 9 h from LPS injection, as evaluated by the reduction of physiologic PDGFRβ expression and the dysfunctional α-SMA increase in peritubular pericytes. The therapeutic intervention by citrate-based coupled plasma filtration adsorption (CPFA) significantly reduced LBP, TGF-β, and endothelin-1 (ET-1) serum levels, and furthermore preserved PDGFRβ and decreased α-SMA expression in renal biopsies. In vitro, both LPS and septic sera led to PMT with a significant increase in Collagen I synthesis and α-SMA reorganization in contractile fibers by both SMAD2/3-dependent and -independent TGF-β signaling. Interestingly, the removal of LBP from septic plasma inhibited PMT. Finally, LPS-stimulated pericytes secreted LBP and TGF-β and underwent PMT also upon TGF-β receptor-blocking, indicating the crucial pro-fibrotic role of TLR4 signaling. Our data demonstrate that the selective removal of LBP may represent a therapeutic option to prevent PMT and the development of acute renal fibrosis in sepsis-induced AKI. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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12 pages, 1936 KiB

Open AccessArticle

Chemokine CXCL13 as a New Systemic Biomarker for B-Cell Involvement in Acute T Cell-Mediated Kidney Allograft Rejection

by Lena Schiffer, Flavia Wiehler, Jan Hinrich Bräsen, Wilfried Gwinner, Robert Greite, Kirill Kreimann, Anja Thorenz, Katja Derlin, Beina Teng, Song Rong, Sibylle von Vietinghoff, Hermann Haller, Michael Mengel, Lars Pape, Christian Lerch, Mario Schiffer and Faikah Gueler

Int. J. Mol. Sci. 2019, 20(10), 2552; https://doi.org/10.3390/ijms20102552 - 24 May 2019

Cited by 15 | Viewed by 4190

Abstract

The presence of B-cell clusters in allogenic T cell-mediated rejection (TCMR) of kidney allografts is linked to more severe disease entities. In this study we characterized B-cell infiltrates in patients with TCMR and examined the role of serum CXCL-13 in these patients and [...] Read more.

The presence of B-cell clusters in allogenic T cell-mediated rejection (TCMR) of kidney allografts is linked to more severe disease entities. In this study we characterized B-cell infiltrates in patients with TCMR and examined the role of serum CXCL-13 in these patients and experimentally. CXCL-13 serum levels were analyzed in 73 kidney allograft recipients at the time of allograft biopsy. In addition, four patients were evaluated for CXCL13 levels during the first week after transplantation. ELISA was done to measure CXCL-13 serum levels. For further mechanistic understanding, a translational allogenic kidney transplant (ktx) mouse model for TCMR was studied in BalbC recipients of fully mismatched transplants with C57BL/6 donor kidneys. CXCL-13 serum levels were measured longitudinally, CD20 and CD3 composition and CXCL13 mRNA in tissue were examined by flow cytometry and kidneys were examined by histology and immunohistochemistry. We found significantly higher serum levels of the B-cell chemoattractant CXCL13 in patients with TCMR compared to controls and patients with borderline TCMR. Moreover, in patients with acute rejection within the first week after ktx, a >5-fold CXCL13 increase was measured and correlated with B-cell infiltrates in the biopsies. In line with the clinical findings, TCMR in mice correlated with increased systemic serum-CXCL13 levels. Moreover, renal allografts had significantly higher CXCL13 mRNA expression than isogenic controls and showed interstitial CD20+ B-cell clusters and CD3+ cell infiltrates accumulating in the vicinity of renal vessels. CXCL13 blood levels correlate with B-cell involvement in TCMR and might help to identify patients at risk of a more severe clinical course of rejection. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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12 pages, 1734 KiB

Open AccessArticle

Renal Regenerative Potential of Extracellular Vesicles Derived from miRNA-Engineered Mesenchymal Stromal Cells

by Marta Tapparo, Stefania Bruno, Federica Collino, Gabriele Togliatto, Maria Chiara Deregibus, Paolo Provero, Sicheng Wen, Peter J. Quesenberry and Giovanni Camussi

Int. J. Mol. Sci. 2019, 20(10), 2381; https://doi.org/10.3390/ijms20102381 - 14 May 2019

Cited by 41 | Viewed by 3661

Abstract

Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) possess pro-regenerative potential in different animal models with renal injury. EVs contain different molecules, including proteins, lipids and nucleic acids. Among the shuttled molecules, miRNAs have a relevant role in the pro-regenerative effects of [...] Read more.

Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) possess pro-regenerative potential in different animal models with renal injury. EVs contain different molecules, including proteins, lipids and nucleic acids. Among the shuttled molecules, miRNAs have a relevant role in the pro-regenerative effects of EVs and are a promising target for therapeutic interventions. The aim of this study was to increase the content of specific miRNAs in EVs that are known to be involved in the pro-regenerative effect of EVs, and to assess the capacity of modified EVs to contribute to renal regeneration in in vivo models with acute kidney injuries. To this purpose, MSCs were transiently transfected with specific miRNA mimics by electroporation. Molecular analyses showed that, after transfection, MSCs and derived EVs were efficiently enriched in the selected miRNAs. In vitro and in vivo experiments indicated that EVs engineered with miRNAs maintained their pro-regenerative effects. Of relevance, engineered EVs were more effective than EVs derived from naïve MSCs when used at suboptimal doses. This suggests the potential use of a low amount of EVs (82.5 × 10⁶) to obtain the renal regenerative effect. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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13 pages, 3254 KiB

Open AccessArticle

Contribution of Inflammatory Cytokine Interleukin-18 Genotypes to Renal Cell Carcinoma

by Wen-Shin Chang, Te-Chun Shen, Wei-Lan Yeh, Chien-Chih Yu, Hui-Yi Lin, Hsi-Chin Wu, Chia-Wen Tsai and Da-Tian Bau

Int. J. Mol. Sci. 2019, 20(7), 1563; https://doi.org/10.3390/ijms20071563 - 28 Mar 2019

Cited by 10 | Viewed by 2568

Abstract

Interleukin-18 (IL-18) is a multi-functional immuno-mediator in the development and progression of many types of infectious and inflammatory diseases. In this study, we evaluated the contribution of IL-18 genotypes to renal cell carcinoma (RCC) in Taiwan via the genotyping of IL-18 [...] Read more.

Interleukin-18 (IL-18) is a multi-functional immuno-mediator in the development and progression of many types of infectious and inflammatory diseases. In this study, we evaluated the contribution of IL-18 genotypes to renal cell carcinoma (RCC) in Taiwan via the genotyping of IL-18 -656 (A/C), -607 (A/C), and -137 (G/C). Moreover, we analyzed their interactions with smoking, alcohol drinking, hypertension, and diabetes status. The results showed an association of the AC and CC genotypes of IL-18 −607 with a significant decrease in the risk of RCC compared with the AA genotype (odds ratio (OR) = 0.44 and 0.35, 95% confidence interval (CI) = 0.27–0.72 and 0.18–0.66, p = 0.0008 and 0.0010, respectively). Furthermore, a significantly lower frequency of the C allele at -607 was observed in the RCC group (35.3% vs. 49.8%; OR = 0.53; 95% CI = 0.35–0.71, p = 0.0003). However, IL-18 -656 and -137 did not exhibit a likewise differential distribution of these genotypes between the control and case groups. Stratifying the population according to smoking, alcohol drinking, hypertension, and diabetes status revealed a different distribution of IL-18 -607 genotypes among non-smokers, non-drinkers, and patients without diabetes, but not among smokers, drinkers, or patients with diabetes. These findings suggest that IL-18 -607 genotypes may play a role in the etiology and progression of RCC in Taiwan and may serve as a useful biomarker for early detection. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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13 pages, 5002 KiB

Open AccessArticle

Change in Renal Glomerular Collagens and Glomerular Filtration Barrier-Related Proteins in a Dextran Sulfate Sodium-Induced Colitis Mouse Model

by Chia-Jung Chang, Pi-Chao Wang, Tzou-Chi Huang and Akiyoshi Taniguchi

Int. J. Mol. Sci. 2019, 20(6), 1458; https://doi.org/10.3390/ijms20061458 - 22 Mar 2019

Cited by 13 | Viewed by 4118

Abstract

Renal disease is not rare among patients with inflammatory bowel disease (IBD) and is gaining interest as a target of research. However, related changes in glomerular structural have rarely been investigated. This study was aimed at clarifying the changes in collagens and glomerular [...] Read more.

Renal disease is not rare among patients with inflammatory bowel disease (IBD) and is gaining interest as a target of research. However, related changes in glomerular structural have rarely been investigated. This study was aimed at clarifying the changes in collagens and glomerular filtration barrier (GFB)-related proteins of glomeruli in a dextran sulfate sodium (DSS)-induced colitis mouse model. Acute colitis was induced by administering 3.5% DSS in Slc:ICR strain mice for eight days. Histological changes to glomeruli were examined by periodic acid-Schiff (PAS) and Masson’s trichrome staining. Expressions of glomerular collagens and GFB-related proteins were analyzed by immunofluorescent staining and Western blot analysis. DSS-colitis mice showed an elevated disease activity index (DAI), colon shortening, massive cellular infiltration and colon damage, confirming that DSS-colitis mice can be used as an IBD animal model. DSS-colitis mice showed increased glycoprotein and collagen deposition in glomeruli. Interestingly, we observed significant changes in glomerular collagens, including a decrease in type IV collagen, and an increment in type I and type V collagens. Moreover, declined GFB-related proteins expressions were detected, including synaptopodin, podocalyxin, nephrin and VE-cadherin. These results suggest that renal disease in DSS-colitis mice might be associated with changes in glomerular collagens and GFB-related proteins. These findings are important for further elucidation of the clinical pathological mechanisms underlying IBD-associated renal disease. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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11 pages, 1776 KiB

Open AccessArticle

Kidney Injury by Variants in the COL4A5 Gene Aggravated by Polymorphisms in Slit Diaphragm Genes Causes Focal Segmental Glomerulosclerosis

by Jenny Frese, Matthias Kettwig, Hildegard Zappel, Johannes Hofer, Hermann-Josef Gröne, Mato Nagel, Gere Sunder-Plassmann, Renate Kain, Jörg Neuweiler and Oliver Gross

Int. J. Mol. Sci. 2019, 20(3), 519; https://doi.org/10.3390/ijms20030519 - 26 Jan 2019

Cited by 14 | Viewed by 3612

Abstract

Kidney injury due to focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disorder causing end-stage renal disease. Homozygous mutations in either glomerular basement membrane or slit diaphragm genes cause early renal failure. Heterozygous carriers develop renal symptoms late, if at all. [...] Read more.

Kidney injury due to focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disorder causing end-stage renal disease. Homozygous mutations in either glomerular basement membrane or slit diaphragm genes cause early renal failure. Heterozygous carriers develop renal symptoms late, if at all. In contrast to mutations in slit diaphragm genes, hetero- or hemizygous mutations in the X-chromosomal COL4A5 Alport gene have not yet been recognized as a major cause of kidney injury by FSGS. We identified cases of FSGS that were unexpectedly diagnosed: In addition to mutations in the X-chromosomal COL4A5 type IV collagen gene, nephrin and podocin polymorphisms aggravated kidney damage, leading to FSGS with ruptures of the basement membrane in a toddler and early renal failure in heterozygous girls. The results of our case series study suggest a synergistic role for genes encoding basement membrane and slit diaphragm proteins as a cause of kidney injury due to FSGS. Our results demonstrate that the molecular genetics of different players in the glomerular filtration barrier can be used to evaluate causes of kidney injury. Given the high frequency of X-chromosomal carriers of Alport genes, the analysis of genes involved in the organization of podocyte architecture, the glomerular basement membrane, and the slit diaphragm will further improve our understanding of the pathogenesis of FSGS and guide prognosis of and therapy for hereditary glomerular kidney diseases. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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Review

Jump to: Editorial, Research

19 pages, 1016 KiB

Open AccessReview

Kidney Cells Regeneration: Dedifferentiation of Tubular Epithelium, Resident Stem Cells and Possible Niches for Renal Progenitors

by Nadezda V. Andrianova, Marina I. Buyan, Ljubava D. Zorova, Irina B. Pevzner, Vasily A. Popkov, Valentina A. Babenko, Denis N. Silachev, Egor Y. Plotnikov and Dmitry B. Zorov

Int. J. Mol. Sci. 2019, 20(24), 6326; https://doi.org/10.3390/ijms20246326 - 15 Dec 2019

Cited by 32 | Viewed by 10751

Abstract

A kidney is an organ with relatively low basal cellular regenerative potential. However, renal cells have a pronounced ability to proliferate after injury, which undermines that the kidney cells are able to regenerate under induced conditions. The majority of studies explain yielded regeneration [...] Read more.

A kidney is an organ with relatively low basal cellular regenerative potential. However, renal cells have a pronounced ability to proliferate after injury, which undermines that the kidney cells are able to regenerate under induced conditions. The majority of studies explain yielded regeneration either by the dedifferentiation of the mature tubular epithelium or by the presence of a resident pool of progenitor cells in the kidney tissue. Whether cells responsible for the regeneration of the kidney initially have progenitor properties or if they obtain a “progenitor phenotype” during dedifferentiation after an injury, still stays the open question. The major stumbling block in resolving the issue is the lack of specific methods for distinguishing between dedifferentiated cells and resident progenitor cells. Transgenic animals, single-cell transcriptomics, and other recent approaches could be powerful tools to solve this problem. This review examines the main mechanisms of kidney regeneration: dedifferentiation of epithelial cells and activation of progenitor cells with special attention to potential niches of kidney progenitor cells. We attempted to give a detailed description of the most controversial topics in this field and ways to resolve these issues. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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21 pages, 675 KiB

Open AccessReview

Renal Benefits of SGLT 2 Inhibitors and GLP-1 Receptor Agonists: Evidence Supporting a Paradigm Shift in the Medical Management of Type 2 Diabetes

by Vjera Ninčević, Tea Omanović Kolarić, Hrvoje Roguljić, Tomislav Kizivat, Martina Smolić and Ines Bilić Ćurčić

Int. J. Mol. Sci. 2019, 20(23), 5831; https://doi.org/10.3390/ijms20235831 - 20 Nov 2019

Cited by 47 | Viewed by 8510

Abstract

Diabetic nephropathy (DN) is one of the most perilous side effects of diabetes mellitus type 1 and type 2 (T1DM and T2DM).). It is known that sodium/glucose cotransporter 2 inhibitors (SGLT 2i) and glucagone like peptide-1 receptor agonists (GLP-1 RAs) have renoprotective effects, [...] Read more.

Diabetic nephropathy (DN) is one of the most perilous side effects of diabetes mellitus type 1 and type 2 (T1DM and T2DM).). It is known that sodium/glucose cotransporter 2 inhibitors (SGLT 2i) and glucagone like peptide-1 receptor agonists (GLP-1 RAs) have renoprotective effects, but the molecular mechanisms are still unknown. In clinical trials GLP-1 analogs exerted important impact on renal composite outcomes, primarily on macroalbuminuria, possibly through suppression of inflammation-related pathways, however enhancement of natriuresis and diuresis is also one of possible mechanisms of nephroprotection. Dapagliflozin, canagliflozin, and empagliflozin are SGLT2i drugs, useful in reducing hyperglycemia and in their potential renoprotective mechanisms, which include blood pressure control, body weight loss, intraglomerular pressure reduction, and a decrease in urinary proximal tubular injury biomarkers. In this review we have discussed the potential synergistic and/or additive effects of GLP 1 RA and SGLT2 inhibitors on the primary onset and progression of kidney disease, and the potential implications on current guidelines of diabetes type 2 management. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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15 pages, 1291 KiB

Open AccessReview

Molecular Mechanisms of the Acute Kidney Injury to Chronic Kidney Disease Transition: An Updated View

by Francesco Guzzi, Luigi Cirillo, Rosa Maria Roperto, Paola Romagnani and Elena Lazzeri

Int. J. Mol. Sci. 2019, 20(19), 4941; https://doi.org/10.3390/ijms20194941 - 06 Oct 2019

Cited by 84 | Viewed by 8183

Abstract

Increasing evidence has demonstrated the bidirectional link between acute kidney injury (AKI) and chronic kidney disease (CKD) such that, in the clinical setting, the new concept of a unified syndrome has been proposed. The pathophysiological reasons, along with the cellular and molecular mechanisms, [...] Read more.

Increasing evidence has demonstrated the bidirectional link between acute kidney injury (AKI) and chronic kidney disease (CKD) such that, in the clinical setting, the new concept of a unified syndrome has been proposed. The pathophysiological reasons, along with the cellular and molecular mechanisms, behind the ability of a single, acute, apparently self-limiting event to drive chronic kidney disease progression are yet to be explained. This acute injury could promote progression to chronic disease through different pathways involving the endothelium, the inflammatory response and the development of fibrosis. The interplay among endothelial cells, macrophages and other immune cells, pericytes and fibroblasts often converge in the tubular epithelial cells that play a central role. Recent evidence has strengthened this concept by demonstrating that injured tubules respond to acute tubular necrosis through two main mechanisms: The polyploidization of tubular cells and the proliferation of a small population of self-renewing renal progenitors. This alternative pathophysiological interpretation could better characterize functional recovery after AKI. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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28 pages, 823 KiB

Open AccessReview

Arachidonic Acid Metabolism and Kidney Inflammation

by Tianqi Wang, Xianjun Fu, Qingfa Chen, Jayanta Kumar Patra, Dongdong Wang, Zhenguo Wang and Zhibo Gai

Int. J. Mol. Sci. 2019, 20(15), 3683; https://doi.org/10.3390/ijms20153683 - 27 Jul 2019

Cited by 216 | Viewed by 18546

Abstract

As a major component of cell membrane lipids, Arachidonic acid (AA), being a major component of the cell membrane lipid content, is mainly metabolized by three kinds of enzymes: cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) enzymes. Based on these three metabolic [...] Read more.

As a major component of cell membrane lipids, Arachidonic acid (AA), being a major component of the cell membrane lipid content, is mainly metabolized by three kinds of enzymes: cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) enzymes. Based on these three metabolic pathways, AA could be converted into various metabolites that trigger different inflammatory responses. In the kidney, prostaglandins (PG), thromboxane (Tx), leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs) are the major metabolites generated from AA. An increased level of prostaglandins (PGs), TxA₂ and leukotriene B4 (LTB₄) results in inflammatory damage to the kidney. Moreover, the LTB₄-leukotriene B4 receptor 1 (BLT1) axis participates in the acute kidney injury via mediating the recruitment of renal neutrophils. In addition, AA can regulate renal ion transport through 19-hydroxystilbenetetraenoic acid (19-HETE) and 20-HETE, both of which are produced by cytochrome P450 monooxygenase. Epoxyeicosatrienoic acids (EETs) generated by the CYP450 enzyme also plays a paramount role in the kidney damage during the inflammation process. For example, 14 and 15-EET mitigated ischemia/reperfusion-caused renal tubular epithelial cell damage. Many drug candidates that target the AA metabolism pathways are being developed to treat kidney inflammation. These observations support an extraordinary interest in a wide range of studies on drug interventions aiming to control AA metabolism and kidney inflammation. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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16 pages, 1887 KiB

Open AccessReview

Efficacy of Polyunsaturated Fatty Acids on Inflammatory Markers in Patients Undergoing Dialysis: A Systematic Review with Network Meta-Analysis of Randomized Clinical Trials

by Po-Kuan Wu, Shu-Ching Yeh, Shan-Jen Li and Yi-No Kang

Int. J. Mol. Sci. 2019, 20(15), 3645; https://doi.org/10.3390/ijms20153645 - 25 Jul 2019

Cited by 9 | Viewed by 2923

Abstract

The effects of polyunsaturated fatty acids (PUFAs) on inflammatory markers among patients receiving dialysis have been discussed for a long time, but previous syntheses made controversial conclusion because of highly conceptual heterogeneity in their synthesis. Thus, to further understanding of this topic, we [...] Read more.

The effects of polyunsaturated fatty acids (PUFAs) on inflammatory markers among patients receiving dialysis have been discussed for a long time, but previous syntheses made controversial conclusion because of highly conceptual heterogeneity in their synthesis. Thus, to further understanding of this topic, we comprehensively gathered relevant randomized clinical trials (RCTs) before April 2019, and two authors independently extracted data of C-reactive protein (CRP), high-sensitivity C-reactive protein (hs-CRP), and interleukin-6 (IL-6) for conducting network meta-analysis. Eighteen eligible RCTs with 962 patients undergoing dialysis were included in our study. The result showed that with placebo as the reference, PUFAs was the only treatment showing significantly lower CRP (weighted mean difference (WMD): −0.37, 95% confidence interval (CI): −0.07 to −0.68), but the CRP in PUFAs group was not significantly lower than vitamin E, PUFAs plus vitamin E, or medium-chain triglyceride. Although no significant changes were noted for hs-CRP and IL-6 levels, PUFAs showed the best ranking among treatments according to surface under the cumulative ranking. Therefore, PUFAs could be a protective option for patients receiving dialysis in clinical practice. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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21 pages, 1761 KiB

Open AccessReview

Cell Death in the Kidney

by Giovanna Priante, Lisa Gianesello, Monica Ceol, Dorella Del Prete and Franca Anglani

Int. J. Mol. Sci. 2019, 20(14), 3598; https://doi.org/10.3390/ijms20143598 - 23 Jul 2019

Cited by 109 | Viewed by 12029

Abstract

Apoptotic cell death is usually a response to the cell’s microenvironment. In the kidney, apoptosis contributes to parenchymal cell loss in the course of acute and chronic renal injury, but does not trigger an inflammatory response. What distinguishes necrosis from apoptosis is the [...] Read more.

Apoptotic cell death is usually a response to the cell’s microenvironment. In the kidney, apoptosis contributes to parenchymal cell loss in the course of acute and chronic renal injury, but does not trigger an inflammatory response. What distinguishes necrosis from apoptosis is the rupture of the plasma membrane, so necrotic cell death is accompanied by the release of unprocessed intracellular content, including cellular organelles, which are highly immunogenic proteins. The relative contribution of apoptosis and necrosis to injury varies, depending on the severity of the insult. Regulated cell death may result from immunologically silent apoptosis or from immunogenic necrosis. Recent advances have enhanced the most revolutionary concept of regulated necrosis. Several modalities of regulated necrosis have been described, such as necroptosis, ferroptosis, pyroptosis, and mitochondrial permeability transition-dependent regulated necrosis. We review the different modalities of apoptosis, necrosis, and regulated necrosis in kidney injury, focusing particularly on evidence implicating cell death in ectopic renal calcification. We also review the evidence for the role of cell death in kidney injury, which may pave the way for new therapeutic opportunities. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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14 pages, 967 KiB

Open AccessReview

The Anti-Inflammatory, Anti-Oxidative, and Anti-Apoptotic Benefits of Stem Cells in Acute Ischemic Kidney Injury

by Kuo-Hua Lee, Wei-Cheng Tseng, Chih-Yu Yang and Der-Cherng Tarng

Int. J. Mol. Sci. 2019, 20(14), 3529; https://doi.org/10.3390/ijms20143529 - 19 Jul 2019

Cited by 49 | Viewed by 5833

Abstract

Ischemia-reperfusion injury (IRI) plays a significant role in the pathogenesis of acute kidney injury (AKI). The complicated interaction between injured tubular cells, activated endothelial cells, and the immune system leads to oxidative stress and systemic inflammation, thereby exacerbating the apoptosis of renal tubular [...] Read more.

Ischemia-reperfusion injury (IRI) plays a significant role in the pathogenesis of acute kidney injury (AKI). The complicated interaction between injured tubular cells, activated endothelial cells, and the immune system leads to oxidative stress and systemic inflammation, thereby exacerbating the apoptosis of renal tubular cells and impeding the process of tissue repair. Stem cell therapy is an innovative approach to ameliorate IRI due to its antioxidative, immunomodulatory, and anti-apoptotic properties. Therefore, it is crucial to understand the biological effects and mechanisms of action of stem cell therapy in the context of acute ischemic AKI to improve its therapeutic benefits. The recent finding that treatment with conditioned medium (CM) derived from stem cells is likely an effective alternative to conventional stem cell transplantation increases the potential for future therapeutic uses of stem cell therapy. In this review, we discuss the recent findings regarding stem cell-mediated cytoprotection, with a focus on the anti-inflammatory effects via suppression of oxidative stress and uncompromised immune responses following AKI. Stem cell-derived CM represents a favorable approach to stem cell-based therapy and may serve as a potential therapeutic strategy against acute ischemic AKI. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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15 pages, 733 KiB

Open AccessReview

Unraveling the Role of Inflammation in the Pathogenesis of Diabetic Kidney Disease

by Keiichiro Matoba, Yusuke Takeda, Yosuke Nagai, Daiji Kawanami, Kazunori Utsunomiya and Rimei Nishimura

Int. J. Mol. Sci. 2019, 20(14), 3393; https://doi.org/10.3390/ijms20143393 - 10 Jul 2019

Cited by 126 | Viewed by 7715

Abstract

Diabetic kidney disease (DKD) remains the leading cause of end-stage renal disease (ESRD) and is therefore a major burden on the healthcare system. Patients with DKD are highly susceptible to developing cardiovascular disease, which contributes to increased morbidity and mortality rates. While progress [...] Read more.

Diabetic kidney disease (DKD) remains the leading cause of end-stage renal disease (ESRD) and is therefore a major burden on the healthcare system. Patients with DKD are highly susceptible to developing cardiovascular disease, which contributes to increased morbidity and mortality rates. While progress has been made to inhibit the acceleration of DKD, current standards of care reduce but do not eliminate the risk of DKD. There is growing appreciation for the role of inflammation in modulating the process of DKD. The focus of this review is on providing an overview of the current status of knowledge regarding the pathologic roles of inflammation in the development of DKD. Finally, we summarize recent therapeutic advances to prevent DKD, with a focus on the anti-inflammatory effects of newly developed agents. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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17 pages, 965 KiB

Open AccessReview

Long Non-Coding RNAs in Kidney Disease

by Michael Ignarski, Rashidul Islam and Roman-Ulrich Müller

Int. J. Mol. Sci. 2019, 20(13), 3276; https://doi.org/10.3390/ijms20133276 - 03 Jul 2019

Cited by 71 | Viewed by 5771

Abstract

Non-coding RNA species contribute more than 90% of all transcripts and have gained increasing attention in the last decade. One of the most recent members of this group are long non-coding RNAs (lncRNAs) which are characterized by a length of more than 200 [...] Read more.

Non-coding RNA species contribute more than 90% of all transcripts and have gained increasing attention in the last decade. One of the most recent members of this group are long non-coding RNAs (lncRNAs) which are characterized by a length of more than 200 nucleotides and a lack of coding potential. However, in contrast to this simple definition, lncRNAs are heterogenous regarding their molecular function—including the modulation of small RNA and protein function, guidance of epigenetic modifications and a role as enhancer RNAs. Furthermore, they show a highly tissue-specific expression pattern. These aspects already point towards an important role in cellular biology and imply lncRNAs as players in development, health and disease. This view has been confirmed by numerous publications from different fields in the last years and has raised the question as to whether lncRNAs may be future therapeutic targets in human disease. Here, we provide a concise overview of the current knowledge on lncRNAs in both glomerular and tubulointerstitial kidney disease. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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19 pages, 1157 KiB

Open AccessReview

Salt Inducible Kinase Signaling Networks: Implications for Acute Kidney Injury and Therapeutic Potential

by Mary Taub

Int. J. Mol. Sci. 2019, 20(13), 3219; https://doi.org/10.3390/ijms20133219 - 30 Jun 2019

Cited by 14 | Viewed by 4526

Abstract

A number of signal transduction pathways are activated during Acute Kidney Injury (AKI). Of particular interest is the Salt Inducible Kinase (SIK) signaling network, and its effects on the Renal Proximal Tubule (RPT), one of the primary targets of injury in AKI. The [...] Read more.

A number of signal transduction pathways are activated during Acute Kidney Injury (AKI). Of particular interest is the Salt Inducible Kinase (SIK) signaling network, and its effects on the Renal Proximal Tubule (RPT), one of the primary targets of injury in AKI. The SIK1 network is activated in the RPT following an increase in intracellular Na⁺ (Na⁺_in), resulting in an increase in Na,K-ATPase activity, in addition to the phosphorylation of Class IIa Histone Deacetylases (HDACs). In addition, activated SIKs repress transcriptional regulation mediated by the interaction between cAMP Regulatory Element Binding Protein (CREB) and CREB Regulated Transcriptional Coactivators (CRTCs). Through their transcriptional effects, members of the SIK family regulate a number of metabolic processes, including such cellular processes regulated during AKI as fatty acid metabolism and mitochondrial biogenesis. SIKs are involved in regulating a number of other cellular events which occur during AKI, including apoptosis, the Epithelial to Mesenchymal Transition (EMT), and cell division. Recently, the different SIK kinase isoforms have emerged as promising drug targets, more than 20 new SIK2 inhibitors and activators having been identified by MALDI-TOF screening assays. Their implementation in the future should prove to be important in such renal disease states as AKI. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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15 pages, 1630 KiB

Open AccessReview

Lysophosphatidic Acid Signaling in Diabetic Nephropathy

by Jong Han Lee, Donghee Kim, Yoon Sin Oh and Hee-Sook Jun

Int. J. Mol. Sci. 2019, 20(11), 2850; https://doi.org/10.3390/ijms20112850 - 11 Jun 2019

Cited by 47 | Viewed by 7377

Abstract

Lysophosphatidic acid (LPA) is a bioactive phospholipid present in most tissues and body fluids. LPA acts through specific LPA receptors (LPAR1 to LPAR6) coupled with G protein. LPA binds to receptors and activates multiple cellular signaling pathways, subsequently exerting various biological functions, such [...] Read more.

Lysophosphatidic acid (LPA) is a bioactive phospholipid present in most tissues and body fluids. LPA acts through specific LPA receptors (LPAR1 to LPAR6) coupled with G protein. LPA binds to receptors and activates multiple cellular signaling pathways, subsequently exerting various biological functions, such as cell proliferation, migration, and apoptosis. LPA also induces cell damage through complex overlapping pathways, including the generation of reactive oxygen species, inflammatory cytokines, and fibrosis. Several reports indicate that the LPA–LPAR axis plays an important role in various diseases, including kidney disease, lung fibrosis, and cancer. Diabetic nephropathy (DN) is one of the most common diabetic complications and the main risk factor for chronic kidney diseases, which mostly progress to end-stage renal disease. There is also growing evidence indicating that the LPA–LPAR axis also plays an important role in inducing pathological alterations of cell structure and function in the kidneys. In this review, we will discuss key mediators or signaling pathways activated by LPA and summarize recent research findings associated with DN. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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21 pages, 620 KiB

Open AccessReview

Mesenchymal Stem Cells—Potential Applications in Kidney Diseases

by Benjamin Bochon, Magdalena Kozubska, Grzegorz Surygała, Agnieszka Witkowska, Roman Kuźniewicz, Władysław Grzeszczak and Grzegorz Wystrychowski

Int. J. Mol. Sci. 2019, 20(10), 2462; https://doi.org/10.3390/ijms20102462 - 18 May 2019

Cited by 58 | Viewed by 6879

Abstract

Mesenchymal stem cells constitute a pool of cells present throughout the lifetime in numerous niches, characteristic of unlimited replication potential and the ability to differentiate into mature cells of mesodermal tissues in vitro. The therapeutic potential of these cells is, however, primarily associated [...] Read more.

Mesenchymal stem cells constitute a pool of cells present throughout the lifetime in numerous niches, characteristic of unlimited replication potential and the ability to differentiate into mature cells of mesodermal tissues in vitro. The therapeutic potential of these cells is, however, primarily associated with their capabilities of inhibiting inflammation and initiating tissue regeneration. Owing to these properties, mesenchymal stem cells (derived from the bone marrow, subcutaneous adipose tissue, and increasingly urine) are the subject of research in the settings of kidney diseases in which inflammation plays the key role. The most advanced studies, with the first clinical trials, apply to ischemic acute kidney injury, renal transplantation, lupus and diabetic nephropathies, in which beneficial clinical effects of cells themselves, as well as their culture medium, were observed. The study findings imply that mesenchymal stem cells act predominantly through secreted factors, including, above all, microRNAs contained within extracellular vesicles. Research over the coming years will focus on this secretome as a possible therapeutic agent void of the potential carcinogenicity of the cells. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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12 pages, 434 KiB

Open AccessReview

Glomerular Hematuria: Cause or Consequence of Renal Inflammation?

by Juan Antonio Moreno, Ángel Sevillano, Eduardo Gutiérrez, Melania Guerrero-Hue, Cristina Vázquez-Carballo, Claudia Yuste, Carmen Herencia, Cristina García-Caballero, Manuel Praga and Jesús Egido

Int. J. Mol. Sci. 2019, 20(9), 2205; https://doi.org/10.3390/ijms20092205 - 05 May 2019

Cited by 41 | Viewed by 8002

Abstract

Glomerular hematuria is a cardinal symptom of renal disease. Glomerular hematuria may be classified as microhematuria or macrohematuria according to the number of red blood cells in urine. Recent evidence suggests a pathological role of persistent glomerular microhematuria in the progression of renal [...] Read more.

Glomerular hematuria is a cardinal symptom of renal disease. Glomerular hematuria may be classified as microhematuria or macrohematuria according to the number of red blood cells in urine. Recent evidence suggests a pathological role of persistent glomerular microhematuria in the progression of renal disease. Moreover, gross hematuria, or macrohematuria, promotes acute kidney injury (AKI), with subsequent impairment of renal function in a high proportion of patients. In this pathological context, hemoglobin, heme, or iron released from red blood cells in the urinary space may cause direct tubular cell injury, oxidative stress, pro-inflammatory cytokine production, and further monocyte/macrophage recruitment. The aim of this manuscript is to review the role of glomerular hematuria in kidney injury, the role of inflammation as cause and consequence of glomerular hematuria, and to discuss novel therapies to combat hematuria. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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12 pages, 1155 KiB

Open AccessReview

Molecular Mechanisms of Kidney Injury and Repair in Arterial Hypertension

by Laura Katharina Sievers and Kai-Uwe Eckardt

Int. J. Mol. Sci. 2019, 20(9), 2138; https://doi.org/10.3390/ijms20092138 - 30 Apr 2019

Cited by 16 | Viewed by 6214

Abstract

The global burden of chronic kidney disease is rising. The etiologies, heterogeneous, and arterial hypertension, are key factors contributing to the development and progression of chronic kidney disease. Arterial hypertension is induced and maintained by a complex network of systemic signaling pathways, such [...] Read more.

The global burden of chronic kidney disease is rising. The etiologies, heterogeneous, and arterial hypertension, are key factors contributing to the development and progression of chronic kidney disease. Arterial hypertension is induced and maintained by a complex network of systemic signaling pathways, such as the hormonal axis of the renin-angiotensin-aldosterone system, hemodynamic alterations affecting blood flow, oxygen supply, and the immune system. This review summarizes the clinical and histopathological features of hypertensive kidney injury and focusses on the interplay of distinct systemic signaling pathways, which drive hypertensive kidney injury in distinct cell types of the kidney. There are several parallels between hypertension-induced molecular signaling cascades in the renal epithelial, endothelial, interstitial, and immune cells. Angiotensin II signaling via the AT1R, hypoxia induced HIFα activation and mechanotransduction are closely interacting and further triggering the adaptions of metabolism, cytoskeletal rearrangement, and profibrotic TGF signaling. The interplay of these, and other cellular pathways, is crucial to balancing the injury and repair of the kidneys and determines the progression of hypertensive kidney disease. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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17 pages, 1260 KiB

Open AccessReview

Pigment Nephropathy: Novel Insights into Inflammasome-Mediated Pathogenesis

by Kurt T. K. Giuliani, Andrew J. Kassianos, Helen Healy and Pedro H. F. Gois

Int. J. Mol. Sci. 2019, 20(8), 1997; https://doi.org/10.3390/ijms20081997 - 23 Apr 2019

Cited by 17 | Viewed by 9734

Abstract

Pigment nephropathy is an acute decline in renal function following the deposition of endogenous haem-containing proteins in the kidneys. Haem pigments such as myoglobin and haemoglobin are filtered by glomeruli and absorbed by the proximal tubules. They cause renal vasoconstriction, tubular obstruction, increased [...] Read more.

Pigment nephropathy is an acute decline in renal function following the deposition of endogenous haem-containing proteins in the kidneys. Haem pigments such as myoglobin and haemoglobin are filtered by glomeruli and absorbed by the proximal tubules. They cause renal vasoconstriction, tubular obstruction, increased oxidative stress and inflammation. Haem is associated with inflammation in sterile and infectious conditions, contributing to the pathogenesis of many disorders such as rhabdomyolysis and haemolytic diseases. In fact, haem appears to be a signalling molecule that is able to activate the inflammasome pathway. Recent studies highlight a pathogenic function for haem in triggering inflammatory responses through the activation of the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome. Among the inflammasome multiprotein complexes, the NLRP3 inflammasome has been the most widely characterized as a trigger of inflammatory caspases and the maturation of interleukin-18 and -1β. In the present review, we discuss the latest evidence on the importance of inflammasome-mediated inflammation in pigment nephropathy. Finally, we highlight the potential role of inflammasome inhibitors in the prophylaxis and treatment of pigment nephropathy. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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24 pages, 780 KiB

Open AccessReview

Non-Coding RNAs as New Therapeutic Targets in the Context of Renal Fibrosis

by Cynthia Van der Hauwaert, François Glowacki, Nicolas Pottier and Christelle Cauffiez

Int. J. Mol. Sci. 2019, 20(8), 1977; https://doi.org/10.3390/ijms20081977 - 23 Apr 2019

Cited by 24 | Viewed by 3511

Abstract

Fibrosis, or tissue scarring, is defined as the excessive, persistent and destructive accumulation of extracellular matrix components in response to chronic tissue injury. Renal fibrosis represents the final stage of most chronic kidney diseases and contributes to the progressive and irreversible decline in [...] Read more.

Fibrosis, or tissue scarring, is defined as the excessive, persistent and destructive accumulation of extracellular matrix components in response to chronic tissue injury. Renal fibrosis represents the final stage of most chronic kidney diseases and contributes to the progressive and irreversible decline in kidney function. Limited therapeutic options are available and the molecular mechanisms governing the renal fibrosis process are complex and remain poorly understood. Recently, the role of non-coding RNAs, and in particular microRNAs (miRNAs), has been described in kidney fibrosis. Seminal studies have highlighted their potential importance as new therapeutic targets and innovative diagnostic and/or prognostic biomarkers. This review will summarize recent scientific advances and will discuss potential clinical applications as well as future research directions. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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16 pages, 1120 KiB

Open AccessReview

Potential and Therapeutic Efficacy of Cell-based Therapy Using Mesenchymal Stem Cells for Acute/chronic Kidney Disease

by Chul Won Yun and Sang Hun Lee

Int. J. Mol. Sci. 2019, 20(7), 1619; https://doi.org/10.3390/ijms20071619 - 01 Apr 2019

Cited by 84 | Viewed by 13989

Abstract

Kidney disease can be either acute kidney injury (AKI) or chronic kidney disease (CKD) and it can lead to the development of functional organ failure. Mesenchymal stem cells (MSCs) are derived from a diverse range of human tissues. They are multipotent and have [...] Read more.

Kidney disease can be either acute kidney injury (AKI) or chronic kidney disease (CKD) and it can lead to the development of functional organ failure. Mesenchymal stem cells (MSCs) are derived from a diverse range of human tissues. They are multipotent and have immunomodulatory effects to assist in the recovery from tissue injury and the inhibition of inflammation. Numerous studies have investigated the feasibility, safety, and efficacy of MSC-based therapies for kidney disease. Although the exact mechanism of MSC-based therapy remains uncertain, their therapeutic value in the treatment of a diverse range of kidney diseases has been studied in clinical trials. The use of MSCs is a promising therapeutic strategy for both acute and chronic kidney disease. The mechanism underlying the effects of MSCs on survival rate after transplantation and functional repair of damaged tissue is still ambiguous. The paracrine effects of MSCs on renal recovery, optimization of the microenvironment for cell survival, and control of inflammatory responses are thought to be related to their interaction with the damaged kidney environment. This review discusses recent experimental and clinical findings related to kidney disease, with a focus on the role of MSCs in kidney disease recovery, differentiation, and microenvironment. The therapeutic efficacy and current applications of MSC-based kidney disease therapies are also discussed. Full article

(This article belongs to the Special Issue Kidney Inflammation, Injury and Regeneration)

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