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Pharmacological Strategies and Molecular Mechanisms Associated with the Novel Nephroprotective Treatments

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (15 March 2024) | Viewed by 11040

Special Issue Editor


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Guest Editor
Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
Interests: epidemiology of Chronic Kidney Disease (CKD): role of prognostic and predictive biomarkers on renal and cardiovascular endpoints; randomized clinical trial design; personalized medicine in nephrology
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Special Issue Information

Dear Colleagues,

Chronic kidney disease (CKD) is a multifactorial disease that is associated with negative endpoints such as regarding mortality, cardiovascular events, and CKD progression to end-stage kidney disease (ESKD).  Starting the appropriate treatment is crucial to improving the prognosis of CKD patients. Recent trials have revealed the efficacy of novel treatments, namely the sodium–glucose cotransporter 2 inhibitors (SLGT2is), the selective antagonists of endothelin receptor A (ERA), and the novel nonsteroidal mineralocorticoid receptor antagonists (MRAs), in reducing cardiorenal risk over time when applied in addition to the standard-of-care therapy. SGLT2is act by restoring kidney tubule–glomerular feedback, improving the extracellular matrix composition (via the suppression of reversion-inducing cysteine rich protein with Kazal motifs (RECK)) and triggering the epithelial-to-mesenchymal transition (via the regulation of numerous metalloproteinases). Moreover, SGLT2is promote kidney fibrosis through different mediators, including p38MAPK, miR-21, IL-1, IL-6, TNF-α, and MCP-1. ERA confers nephroprotection by blocking molecular pathways that lead to vasoconstrictions, podocyte activation, inflammation, and oxidative stress. They also modulate extracellular matrix deposition via the inhibition of NF-ĸB and TGF-β patterns. The novel MRAs contribute to reducing CKD progression by inducing serum glucocorticoid kinase (Sgk1) activity, which promotes natriuresis, and by reducing fibrosis and inflammation.

Hence, cardiorenal protection occurs due to the reduction in albuminuria in the first months after starting treatment, but several other mechanisms (anti-inflammatory, antifibrotic, hemodynamic) have been proposed and should be more thoroughly characterized. Moreover, it has recently been shown that the combination of two or more of these drugs can provide additional positive effects in terms of reducing albuminuria and conferring nephroprotection.

This Special Issue aims to discuss the molecular mechanisms underlying the efficacy of novel nephroprotective treatments and to understand the types of kidney diseases or patient profiles for which specific treatment combinations can be potentially most effective. All types of study designs will be considered, including original scientific research articles, comprehensive reviews, and communications.

Dr. Michele Provenzano
Guest Editor

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Keywords

  • albuminuria
  • chronic kidney disease
  • cardiovascular risk
  • renal progression
  • SGLT2i
  • MRA
  • ERA

Published Papers (5 papers)

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Research

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14 pages, 4673 KiB  
Article
Suppression of Indoxyl Sulfate Accumulation Reduces Renal Fibrosis in Sulfotransferase 1a1-Deficient Mice
by Huixian Hou, Mai Horikawa, Yuki Narita, Hirofumi Jono, Yutaka Kakizoe, Yuichiro Izumi, Takashige Kuwabara, Masashi Mukoyama and Hideyuki Saito
Int. J. Mol. Sci. 2023, 24(14), 11329; https://doi.org/10.3390/ijms241411329 - 11 Jul 2023
Cited by 2 | Viewed by 1786
Abstract
Renal fibrosis is the final manifestation of chronic kidney disease (CKD); its prevention is vital for controlling CKD progression. Indoxyl sulfate (IS), a typical sulfate-conjugated uremic solute, is produced in the liver via the enzyme sulfotransferase (SULT) 1A1 and accumulates significantly during CKD. [...] Read more.
Renal fibrosis is the final manifestation of chronic kidney disease (CKD); its prevention is vital for controlling CKD progression. Indoxyl sulfate (IS), a typical sulfate-conjugated uremic solute, is produced in the liver via the enzyme sulfotransferase (SULT) 1A1 and accumulates significantly during CKD. We investigated the toxicopathological role of IS in renal fibrosis using Sult1a1-KO mice and the underlying mechanisms. The unilateral ureteral obstruction (UUO) model was created; kidney IS concentrations, inflammation, and renal fibrosis were assessed on day 14. After UUO treatment, inflammation and renal fibrosis were exacerbated in WT mice, with an accumulation of IS in the kidney. However, they were significantly suppressed in Sult1a1-KO mice. CD206+ expression was upregulated, and β-catenin expression was downregulated in Sult1a1-KO mice. To confirm the impact of erythropoietin (EPO) on renal fibrosis, we evaluated the time-dependent expression of EPO. In Sult1a1-KO mice, EPO mRNA expression was improved considerably; UUO-induced renal fibrosis was further attenuated by recombinant human erythropoietin (rhEPO). Thus, UUO-induced renal fibrosis was alleviated in Sult1a1-KO mice with a decreased accumulation of IS. Our findings confirmed the pathological role of IS in renal fibrosis and identified SULT1A1 as a new therapeutic target enzyme for preventing and attenuating renal fibrosis. Full article
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18 pages, 711 KiB  
Article
Assessment of Renal Function in Head and Neck Cancer Patients Treated with Cisplatin: Different Biomarkers and Acute Kidney Injury Classifications
by Nadine de Godoy Torso, Marília Berlofa Visacri, Julia Coelho França Quintanilha, Maria Aparecida Cursino, Eder de Carvalho Pincinato and Patricia Moriel
Int. J. Mol. Sci. 2023, 24(1), 141; https://doi.org/10.3390/ijms24010141 - 21 Dec 2022
Cited by 3 | Viewed by 2025
Abstract
Cisplatin is associated with dose-limiting nephrotoxicity, and the timely detection of acute kidney injury (AKI) can affect morbimortality. Therefore, this study aimed to investigate the tools for monitoring renal function in AKI. This was a retrospective, cohort study. Cisplatin-treated patients with head and [...] Read more.
Cisplatin is associated with dose-limiting nephrotoxicity, and the timely detection of acute kidney injury (AKI) can affect morbimortality. Therefore, this study aimed to investigate the tools for monitoring renal function in AKI. This was a retrospective, cohort study. Cisplatin-treated patients with head and neck cancer were included. Nephrotoxicity was assessed using serum creatinine, estimated creatinine clearance, serum electrolytic alterations, and plasma kidney injury molecule-1 (KIM-1). The toxicity severity was classified according to Common Terminology Criteria for Adverse Events (CTCAE), and AKI was classified by Risk, Injury, Failure, Loss, and End-stage kidney disease (RIFLE) and Acute Kidney Injury Network (AKIN). A total of 81 participants were included, of whom only 32 did not have AKI. Almost 90% of participants had a decreased estimated glomerular filtration rate five (D5) days after chemotherapy. The AKI estimate differs between AKIN and RIFLE; more participants were diagnosed by the RIFLE at D5, 19.5% versus 2.4% by AKIN, and fifteen had a discordance between these classifications. All laboratory markers showed significant changes on D5. KIM-1 appeared a possible biomarker when considering CTCAE or AKIN classifications (p < 0.05 on D5), but not when RIFLE classification was used (p = 0.0780). Further studies may seek to understand the profiles of different biomarkers together. Full article
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Review

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15 pages, 760 KiB  
Review
Renin–Angiotensin–Aldosterone System: From History to Practice of a Secular Topic
by Sara H. Ksiazek, Lilio Hu, Sebastiano Andò, Markus Pirklbauer, Marcus D. Säemann, Chiara Ruotolo, Gianluigi Zaza, Gaetano La Manna, Luca De Nicola, Gert Mayer and Michele Provenzano
Int. J. Mol. Sci. 2024, 25(7), 4035; https://doi.org/10.3390/ijms25074035 - 04 Apr 2024
Viewed by 633
Abstract
Renin–angiotensin–aldosterone system (RAAS) inhibitors are standard care in patients with hypertension, heart failure or chronic kidney disease (CKD). Although we have studied the RAAS for decades, there are still circumstances that remain unclear. In this review, we describe the evolution of the RAAS [...] Read more.
Renin–angiotensin–aldosterone system (RAAS) inhibitors are standard care in patients with hypertension, heart failure or chronic kidney disease (CKD). Although we have studied the RAAS for decades, there are still circumstances that remain unclear. In this review, we describe the evolution of the RAAS and pose the question of whether this survival trait is still necessary to humankind in the present age. We elucidate the benefits on cardiovascular health and kidney disease of RAAS inhibition and present promising novel medications. Furthermore, we address why more studies are needed to establish a new standard of care away from generally prescribing ACEi or ARB toward an improved approach to combine drugs tailored to the needs of individual patients. Full article
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21 pages, 409 KiB  
Review
New Insights into the Nephroprotective Potential of Lercanidipine
by Joanna Hajdys, Piotr Fularski, Klaudia Leszto, Gabriela Majchrowicz, Magdalena Stabrawa, Ewelina Młynarska, Jacek Rysz and Beata Franczyk
Int. J. Mol. Sci. 2023, 24(18), 14048; https://doi.org/10.3390/ijms241814048 - 13 Sep 2023
Viewed by 3134
Abstract
Kidneys are responsible for many crucial biological processes in the human body, including maintaining the water–electrolyte balance, pH, and blood pressure (BP), along with the elimination of toxins. Despite this, chronic kidney disease (CKD), which affects more and more people, is a disease [...] Read more.
Kidneys are responsible for many crucial biological processes in the human body, including maintaining the water–electrolyte balance, pH, and blood pressure (BP), along with the elimination of toxins. Despite this, chronic kidney disease (CKD), which affects more and more people, is a disease that develops insidiously without causing any symptoms at first. The main purpose of this article is to summarize the existing literature on lercanidipine, with a particular focus on its nephroprotective properties. Lercanidipine is a third-generation dihydropyridine (DHP) blocker of calcium channels, and as such it possesses unique qualities such as high lipophilicity and high vascular selectivity. Furthermore, it acts by reversibly inhibiting L-type and T-type calcium channels responsible for exerting positive renal effects. It has been shown to reduce tissue inflammation and tubulointerstitial fibrosis, contributing to a decrease in proteinuria. Moreover, it exhibited antioxidative effects and increased expression of molecules responsible for repairing damaged tissues. It also decreased cell proliferation, preventing thickening of the vascular lumen. This article summarizes studies simultaneously comparing the effect of lercanidipine with other antihypertensive drugs. There is still a lack of studies on the medications used in patients with CKD, and an even greater lack of studies on those used in patients with concomitant hypertension. Therefore, further studies on lercanidipine and its potential in hypertensive patients with coexisting CKD are required. Full article
17 pages, 883 KiB  
Review
Critical Overview of Hepatic Factors That Link Non-Alcoholic Fatty Liver Disease and Acute Kidney Injury: Physiology and Therapeutic Implications
by Le Chen, Xiaodong Lv, Min Kan, Ruonan Wang, Hua Wang and Hongmei Zang
Int. J. Mol. Sci. 2022, 23(20), 12464; https://doi.org/10.3390/ijms232012464 - 18 Oct 2022
Cited by 3 | Viewed by 2558
Abstract
Non-alcoholic fatty liver disease (NAFLD) is defined as a combination of a group of progressive diseases, presenting different structural features of the liver at different stages of the disease. According to epidemiological surveys, as living standards improve, the global prevalence of NAFLD increases. [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is defined as a combination of a group of progressive diseases, presenting different structural features of the liver at different stages of the disease. According to epidemiological surveys, as living standards improve, the global prevalence of NAFLD increases. Acute kidney injury (AKI) is a class of clinical conditions characterized by a rapid decline in kidney function. NAFLD and AKI, as major public health diseases with high prevalence and mortality, respectively, worldwide, place a heavy burden on societal healthcare systems. Clinical observations of patients with NAFLD with AKI suggest a possible association between the two diseases. However, little is known about the pathogenic mechanisms linking NAFLD and AKI, and the combination of the diseases is poorly treated. Previous studies have revealed that liver-derived factors are transported to distal organs via circulation, such as the kidney, where they elicit specific effects. Of note, while NAFLD affects the expression of many hepatic factors, studies on the mechanisms whereby NAFLD mediates the generation of hepatic factors that lead to AKI are lacking. Considering the unique positioning of hepatic factors in coordinating systemic energy metabolism and maintaining energy homeostasis, we hypothesize that the effects of NAFLD are not only limited to the structural and functional changes in the liver but may also involve the entire body via the hepatic factors, e.g., playing an important role in the development of AKI. This raises the question of whether analogs of beneficial hepatic factors or inhibitors of detrimental hepatic factors could be used as a treatment for NAFLD-mediated and hepatic factor-driven AKI or other metabolic disorders. Accordingly, in this review, we describe the systemic effects of several types of hepatic factors, with a particular focus on the possible link between hepatic factors whose expression is altered under NAFLD and AKI. We also summarize the role of some key hepatic factors in metabolic control mechanisms and discuss their possible use as a preventive treatment for the progression of metabolic diseases. Full article
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