International Journal of Molecular Sciences

Research

17 pages, 1689 KiB

Open AccessArticle

Fibrocystin Is Essential to Cellular Control of Adhesion and Epithelial Morphogenesis

by Wolfgang H. Ziegler, Birga Soetje, Lisa P. Marten, Jana Wiese, Mithila Burute and Dieter Haffner

Int. J. Mol. Sci. 2020, 21(14), 5140; https://doi.org/10.3390/ijms21145140 - 20 Jul 2020

Cited by 9 | Viewed by 2407

Abstract

Mutations of the Pkhd1 gene cause autosomal recessive polycystic kidney disease (ARPKD). Pkhd1 encodes fibrocystin/polyductin (FPC), a ciliary type I membrane protein of largely unknown function, suggested to affect adhesion signaling of cells. Contributions of epithelial cell adhesion and contractility to the disease [...] Read more.

Mutations of the Pkhd1 gene cause autosomal recessive polycystic kidney disease (ARPKD). Pkhd1 encodes fibrocystin/polyductin (FPC), a ciliary type I membrane protein of largely unknown function, suggested to affect adhesion signaling of cells. Contributions of epithelial cell adhesion and contractility to the disease process are elusive. Here, we link loss of FPC to defective epithelial morphogenesis in 3D cell culture and altered cell contact formation. We study Pkhd1-silenced Madin-Darby Canine Kidney II (MDCKII) cells using an epithelial morphogenesis assay based on micropatterned glass coverslips. The assay allows analysis of cell adhesion, polarity and lumen formation of epithelial spheroids. Pkhd1 silencing critically affects the initial phase of the morphogenesis assay, leading to a reduction of correctly polarized spheroids by two thirds. Defects are characterized by altered cell adhesion and centrosome positioning of FPC-deficient cells in their 1-/2-cell stages. When myosin II inhibitor is applied to reduce cellular tension during the critical early phase of the assay, Pkhd1 silencing no longer inhibits formation of correctly polarized epithelia. We propose that altered sensing and cell interaction of FPC-deficient epithelial cells promote progressive epithelial defects in ARPKD. Full article

(This article belongs to the Special Issue Comorbidities in Chronic Diseases: Molecular Markers and Therapies)

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14 pages, 2869 KiB

Open AccessArticle

Innovative Three-Dimensional Microscopic Analysis of Uremic Growth Plate Discloses Alterations in the Process of Chondrocyte Hypertrophy: Effects of Growth Hormone Treatment

by Ángela Fernández-Iglesias, Rocío Fuente, Helena Gil-Peña, Laura Alonso-Durán, María García-Bengoa, Fernando Santos and José Manuel López

Int. J. Mol. Sci. 2020, 21(12), 4519; https://doi.org/10.3390/ijms21124519 - 25 Jun 2020

Cited by 3 | Viewed by 2583

Abstract

Chronic kidney disease (CKD) alters the morphology and function of the growth plate (GP) of long bones by disturbing chondrocyte maturation. GP chondrocytes were analyzed in growth-retarded young rats with CKD induced by adenine intake (AD), control rats fed ad libitum (C) or [...] Read more.

Chronic kidney disease (CKD) alters the morphology and function of the growth plate (GP) of long bones by disturbing chondrocyte maturation. GP chondrocytes were analyzed in growth-retarded young rats with CKD induced by adenine intake (AD), control rats fed ad libitum (C) or pair-fed with the AD group (PF), and CKD rats treated with growth hormone (ADGH). In order to study the alterations in the process of GP maturation, we applied a procedure recently described by our group to obtain high-quality three-dimensional images of whole chondrocytes that can be used to analyze quantitative parameters like cytoplasm density, cell volume, and shape. The final chondrocyte volume was found to be decreased in AD rats, but GH treatment was able to normalize it. The pattern of variation in the cell cytoplasm density suggests that uremia could be causing a delay to the beginning of the chondrocyte hypertrophy process. Growth hormone treatment appears to be able to compensate for this disturbance by triggering an early chondrocyte enlargement that may be mediated by Nkcc1 action, an important membrane cotransporter in the GP chondrocyte enlargement. Full article

(This article belongs to the Special Issue Comorbidities in Chronic Diseases: Molecular Markers and Therapies)

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17 pages, 1438 KiB

Open AccessArticle

Single-Nucleotide Polymorphisms (SNPs) Both Associated with Hypertension and Contributing to Accelerated-Senescence Traits in OXYS Rats

by Vasiliy A. Devyatkin, Olga E. Redina, Natalia A. Muraleva and Nataliya G. Kolosova

Int. J. Mol. Sci. 2020, 21(10), 3542; https://doi.org/10.3390/ijms21103542 - 17 May 2020

Cited by 6 | Viewed by 2404

Abstract

Aging is a major risk factor of numerous human diseases. Adverse genetic variants may contribute to multiple manifestations of aging and increase the number of comorbid conditions. There is evidence of links between hypertension and age-related diseases, although the genetic relationships are insufficiently [...] Read more.

Aging is a major risk factor of numerous human diseases. Adverse genetic variants may contribute to multiple manifestations of aging and increase the number of comorbid conditions. There is evidence of links between hypertension and age-related diseases, although the genetic relationships are insufficiently studied. Here, we investigated the contribution of hypertension to the development of accelerated-senescence syndrome in OXYS rats. We compared transcriptome sequences of the prefrontal cortex, hippocampus, and retina of OXYS rats with the genotypes of 45 rat strains and substrains (which include models with hypertension) to find single-nucleotide polymorphisms (SNPs) both associated with hypertension and possibly contributing to the development of age-related diseases. A total of 725 polymorphisms were common between OXYS rats and one or more hypertensive rat strains/substrains being analyzed. Multidimensional scaling detected significant similarities between OXYS and ISIAH rat genotypes and significant differences between these strains and the other hypertensive rat strains/substrains. Nonetheless, similar sets of SNPs produce a different phenotype in OXYS and ISIAH rats depending on hypertension severity. We identified 13 SNPs causing nonsynonymous amino-acid substitutions having a deleterious effect on the structure or function of the corresponding proteins and four SNPs leading to functionally significant structural rearrangements of transcripts in OXYS rats. Among them, SNPs in genes Ephx1, Pla2r1, and Ccdc28b were identified as candidates responsible for the concomitant manifestation of hypertension and signs of accelerated aging in OXYS rats. Full article

(This article belongs to the Special Issue Comorbidities in Chronic Diseases: Molecular Markers and Therapies)

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23 pages, 3997 KiB

Open AccessArticle

High-Protein Diet Induces Hyperuricemia in a New Animal Model for Studying Human Gout

by Fan Hong, Aijuan Zheng, Pengfei Xu, Jialin Wang, Tingting Xue, Shu Dai, Shijia Pan, Yuan Guo, Xinlu Xie, Letong Li, Xiaoxiao Qiao, Guohua Liu and Yonggong Zhai

Int. J. Mol. Sci. 2020, 21(6), 2147; https://doi.org/10.3390/ijms21062147 - 20 Mar 2020

Cited by 36 | Viewed by 9374

Abstract

Hyperuricemia is a central risk factor for gout and increases the risk for other chronic diseases, including cardiometabolic disease, kidney disease, and hypertension. Overproduction of urate is one of the main reasons for hyperuricemia, and dietary factors including seafoods, meats, and drinking are [...] Read more.

Hyperuricemia is a central risk factor for gout and increases the risk for other chronic diseases, including cardiometabolic disease, kidney disease, and hypertension. Overproduction of urate is one of the main reasons for hyperuricemia, and dietary factors including seafoods, meats, and drinking are contributed to the development of it. However, the lack of a suitable animal model for urate metabolism is one of the main reasons for the delay and limitations of hyperuricemia research. Combining evolutionary biological studies and clinical studies, we conclude that chicken is a preferred animal model for hyperuricemia. Thus, we provided chickens a high-protein diet (HPD) to evaluate the changes in the serum urate levels in chickens. In our study, the HPD increased the serum urate level and maintained it at a long-term high level in chickens. Long-term high serum urate levels induced an abnormal chicken claw morphology and the precipitation of monosodium urate (MSU) in joint synovial fluid. In addition, a long-term HPD also decreased the glomerular filtration rate and induced mild renal injury. Most importantly, allopurinol and probenecid displayed the positive effects in decreasing serum urate and then attenuated hyperuricemia in chicken model. These findings provide a novel model for hyperuricemia and a new opportunity to further investigate the effects of long-term hyperuricemia on other metabolic diseases. Full article

(This article belongs to the Special Issue Comorbidities in Chronic Diseases: Molecular Markers and Therapies)

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Review

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15 pages, 589 KiB

Open AccessReview

Vitamin D and Cardiovascular Disease, with Emphasis on Hypertension, Atherosclerosis, and Heart Failure

by Nejla Latic and Reinhold G. Erben

Int. J. Mol. Sci. 2020, 21(18), 6483; https://doi.org/10.3390/ijms21186483 - 4 Sep 2020

Cited by 133 | Viewed by 12526

Abstract

Vitamin D deficiency is the most common nutritional deficiency, affecting almost one billion people worldwide. Vitamin D is mostly known for its role in intestinal calcium absorption and bone mineralization. However, the observation of seasonal changes in blood pressure and the subsequent identification [...] Read more.

Vitamin D deficiency is the most common nutritional deficiency, affecting almost one billion people worldwide. Vitamin D is mostly known for its role in intestinal calcium absorption and bone mineralization. However, the observation of seasonal changes in blood pressure and the subsequent identification of vitamin D receptor (VDR) and 1α-hydroxylase in cardiomyocytes, as well as endothelial and vascular smooth muscle cells, implicated a role of vitamin D in the cardiovascular system. Animal studies provided compelling evidence that vitamin D signaling is essential for cardiovascular integrity, especially for the regulation of vascular tone and as an antifibrotic and antihypertrophic signaling pathway in the heart. In addition, observational studies reported an association between vitamin D deficiency and risk of hypertension, atherosclerosis, and heart failure. However, recent clinical intervention studies failed to prove the causal relationship between vitamin D supplementation and beneficial effects on cardiovascular health. In this review, we aim to highlight our current understanding of the role of vitamin D in the cardiovascular system and to find potential explanations for the large discrepancies between the outcome of experimental studies and clinical intervention trials. Full article

(This article belongs to the Special Issue Comorbidities in Chronic Diseases: Molecular Markers and Therapies)

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17 pages, 1096 KiB

Open AccessReview

Metabolic Changes in Polycystic Kidney Disease as a Potential Target for Systemic Treatment

by Sophie Haumann, Roman-Ulrich Müller and Max C. Liebau

Int. J. Mol. Sci. 2020, 21(17), 6093; https://doi.org/10.3390/ijms21176093 - 24 Aug 2020

Cited by 8 | Viewed by 4642

Abstract

Autosomal recessive and autosomal dominant polycystic kidney disease (ARPKD, ADPKD) are systemic disorders with pronounced hepatorenal phenotypes. While the main underlying genetic causes of both ARPKD and ADPKD have been well-known for years, the exact molecular mechanisms resulting in the observed clinical phenotypes [...] Read more.

Autosomal recessive and autosomal dominant polycystic kidney disease (ARPKD, ADPKD) are systemic disorders with pronounced hepatorenal phenotypes. While the main underlying genetic causes of both ARPKD and ADPKD have been well-known for years, the exact molecular mechanisms resulting in the observed clinical phenotypes in the different organs, remain incompletely understood. Recent research has identified cellular metabolic changes in PKD. These findings are of major relevance as there may be an immediate translation into clinical trials and potentially clinical practice. Here, we review important results in the field regarding metabolic changes in PKD and their modulation as a potential target of systemic treatment. Full article

(This article belongs to the Special Issue Comorbidities in Chronic Diseases: Molecular Markers and Therapies)

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19 pages, 1195 KiB

Open AccessReview

Molecular Mechanism Contributing to Malnutrition and Sarcopenia in Patients with Liver Cirrhosis

by Fatuma Meyer, Karen Bannert, Mats Wiese, Susanne Esau, Lea F. Sautter, Luise Ehlers, Ali A. Aghdassi, Cornelia C. Metges, Leif-A. Garbe, Robert Jaster, Markus M. Lerch, Georg Lamprecht and Luzia Valentini

Int. J. Mol. Sci. 2020, 21(15), 5357; https://doi.org/10.3390/ijms21155357 - 28 Jul 2020

Cited by 50 | Viewed by 11973

Abstract

Liver cirrhosis is frequently accompanied by disease-related malnutrition (DRM) and sarcopenia, defined as loss of skeletal muscle mass and function. DRM and sarcopenia often coexist in cirrhotic patients and are associated with increased morbidity and mortality. The clinical manifestation of both comorbidities are [...] Read more.

Liver cirrhosis is frequently accompanied by disease-related malnutrition (DRM) and sarcopenia, defined as loss of skeletal muscle mass and function. DRM and sarcopenia often coexist in cirrhotic patients and are associated with increased morbidity and mortality. The clinical manifestation of both comorbidities are triggered by multifactorial mechanisms including reduced nutrient and energy intake caused by dietary restrictions, anorexia, neuroendocrine deregulation, olfactory and gustatory deficits. Maldigestion and malabsorption due to small intestinal bacterial overgrowth, pancreatic insufficiency or cholestasis may also contribute to DRM and sarcopenia. Decreased protein synthesis and increased protein degradation is the cornerstone mechanism to muscle loss, among others mediated by disease- and inflammation-mediated metabolic changes, hyperammonemia, increased myostatin and reduced human growth hormone. The concise pathophysiological mechanisms and interactions of DRM and sarcopenia in liver cirrhosis are not completely understood. Furthermore, most knowledge in this field are based on experimental models, but only few data in humans exist. This review summarizes known and proposed molecular mechanisms contributing to malnutrition and sarcopenia in liver cirrhosis and highlights remaining knowledge gaps. Since, in the prevention and treatment of DRM and sarcopenia in cirrhotic patients, more research is needed to identify potential biomarkers for diagnosis and development of targeted therapeutic strategies. Full article

(This article belongs to the Special Issue Comorbidities in Chronic Diseases: Molecular Markers and Therapies)

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11 pages, 1412 KiB

Open AccessReview

Bone Disease in Nephropathic Cystinosis: Beyond Renal Osteodystrophy

by Irma Machuca-Gayet, Thomas Quinaux, Aurélia Bertholet-Thomas, Ségolène Gaillard, Débora Claramunt-Taberner, Cécile Acquaviva-Bourdain and Justine Bacchetta

Int. J. Mol. Sci. 2020, 21(9), 3109; https://doi.org/10.3390/ijms21093109 - 28 Apr 2020

Cited by 15 | Viewed by 3260

Abstract

Patients with chronic kidney disease (CKD) display significant mineral and bone disorders (CKD-MBD) that induce significant cardiovascular, growth and bone comorbidities. Nephropathic cystinosis is an inherited metabolic disorder caused by the lysosomal accumulation of cystine due to mutations in the CTNS gene encoding [...] Read more.

Patients with chronic kidney disease (CKD) display significant mineral and bone disorders (CKD-MBD) that induce significant cardiovascular, growth and bone comorbidities. Nephropathic cystinosis is an inherited metabolic disorder caused by the lysosomal accumulation of cystine due to mutations in the CTNS gene encoding cystinosin, and leads to end-stage renal disease within the second decade. The cornerstone of management relies on cysteamine therapy to decrease lysosomal cystine accumulation in target organs. However, despite cysteamine therapy, patients display severe bone symptoms, and the concept of “cystinosis metabolic bone disease” is currently emerging. Even though its exact pathophysiology remains unclear, at least five distinct but complementary entities can explain bone impairment in addition to CKD-MBD: long-term consequences of renal Fanconi syndrome, malnutrition and copper deficiency, hormonal disturbances, myopathy, and intrinsic/iatrogenic bone defects. Direct effects of both CTNS mutation and cysteamine on osteoblasts and osteoclasts are described. Thus, the main objective of this manuscript is not only to provide a clinical update on bone disease in cystinosis, but also to summarize the current experimental evidence demonstrating a functional impairment of bone cells in this disease and to discuss new working hypotheses that deserve future research in the field. Full article

(This article belongs to the Special Issue Comorbidities in Chronic Diseases: Molecular Markers and Therapies)

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Other

Jump to: Research, Review

7 pages, 716 KiB

Open AccessCase Report

Diabetes Mellitus and Hypertension—A Case of Sugar and Salt?

by Marcus Sondermann, Michał Holecki, Andrea Marita Kirsch, Manuela Bastian, Dagmar-Christiane Fischer and Holger Sven Willenberg

Int. J. Mol. Sci. 2020, 21(15), 5200; https://doi.org/10.3390/ijms21155200 - 22 Jul 2020

Cited by 3 | Viewed by 3902

Abstract

The majority of patients with diabetes mellitus (DM) have hypertension (HTN). A specific mechanism for the development of HTN in DM has not been described. In the Zucker, Endothel, und Salz (sugar, endothelium, and salt) study (ZEuS), indices of glucose metabolism and of [...] Read more.

The majority of patients with diabetes mellitus (DM) have hypertension (HTN). A specific mechanism for the development of HTN in DM has not been described. In the Zucker, Endothel, und Salz (sugar, endothelium, and salt) study (ZEuS), indices of glucose metabolism and of volume regulation are recorded. An analysis of these parameters shows that glucose concentrations interfere with plasma osmolality and that changes in glycemic control have a significant impact on fluid status and blood pressure. The results of this study are discussed against the background of the striking similarities between the regulation of sugar and salt blood concentrations, introducing the view that DM is probably a sodium-retention disorder that leads to a state of hypervolemia. Full article

(This article belongs to the Special Issue Comorbidities in Chronic Diseases: Molecular Markers and Therapies)

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