Progression of chronic kidney disease: too much cellular talk causes damage

Gewin, Leslie; Zent, Roy; Pozzi, Ambra

doi:10.1016/j.kint.2016.08.025

Cited by 113 publications

(96 citation statements)

References 104 publications

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“…Nevertheless, our results give an overview of genes and pathways that are modulated by shear stress in renal epithelial cells, which could help us to understand relevant biological processes involved in mechano‐sensing. Several of the shear regulated processes are altered in kidney diseases as well, including TGF‐β, Wnt, and JAK‐STAT signaling (Gewin, Zent, & Pozzi, ). We hypothesize that large variations in shear stress, occurring in kidney diseases, might contribute to the disease phenotype.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive transcriptome analysis of fluid shear stress altered gene expression in renal epithelial cells

Kunnen

Malas

Semeins

et al. 2017

Journal Cellular Physiology

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Renal epithelial cells are exposed to mechanical forces due to flow‐induced shear stress within the nephrons. Shear stress is altered in renal diseases caused by tubular dilation, obstruction, and hyperfiltration, which occur to compensate for lost nephrons. Fundamental in regulation of shear stress are primary cilia and other mechano‐sensors, and defects in cilia formation and function have profound effects on development and physiology of kidneys and other organs. We applied RNA sequencing to get a comprehensive overview of fluid‐shear regulated genes and pathways in renal epithelial cells. Functional enrichment‐analysis revealed TGF‐β, MAPK, and Wnt signaling as core signaling pathways up‐regulated by shear. Inhibitors of TGF‐β and MAPK/ERK signaling modulate a wide range of mechanosensitive genes, identifying these pathways as master regulators of shear‐induced gene expression. However, the main down‐regulated pathway, that is, JAK/STAT, is independent of TGF‐β and MAPK/ERK. Other up‐regulated cytokine pathways include FGF, HB‐EGF, PDGF, and CXC. Cellular responses to shear are modified at several levels, indicated by altered expression of genes involved in cell‐matrix, cytoskeleton, and glycocalyx remodeling, as well as glycolysis and cholesterol metabolism. Cilia ablation abolished shear induced expression of a subset of genes, but genes involved in TGF‐β, MAPK, and Wnt signaling were hardly affected, suggesting that other mechano‐sensors play a prominent role in the shear stress response of renal epithelial cells. Modulations in signaling due to variations in fluid shear stress are relevant for renal physiology and pathology, as suggested by elevated gene expression at pathological levels of shear stress compared to physiological shear.

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Section: Discussionmentioning

confidence: 99%

Comprehensive transcriptome analysis of fluid shear stress altered gene expression in renal epithelial cells

Kunnen

Malas

Semeins

et al. 2017

Journal Cellular Physiology

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“…It affects 10% of adult population, and the prevalence of CKD is still increasing because of population aging, diabetes, hypertension, and other causes (1,2). Tubulointerstitial fibrosis is a major hallmark of CKD, which is driven by renal tubule injuries (3). After severe or recurrent injuries, renal tubular epithelial cells undergo changes with production of profibrotic cytokines, which initiate fibrotic responses (4).…”

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confidence: 99%

Reduced asymmetric dimethylarginine accumulation through inhibition of the type I protein arginine methyltransferases promotes renal fibrosis in obstructed kidneys

Peng

Lin

et al. 2019

FASEB j.

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The role of asymmetric dimethylarginine (ADMA) in chronic kidney disease (CKD) is unclear. Through inhibition of type I protein arginine methyltransferases (PRMTs), a novel strategy, we aimed to determine the effect of ADMA on renal fibrosis and explore its underlying working mechanisms. After sham or unilateral ureter ligation (UUO) operation, 20–25 g male c57 mice were treated with vehicle or PT1001B, an inhibitor of type I PRMTs, for 13 d. Moreover, human kidney 2 (HK2) and normal rat kidney 49F (NRK‐49F) cells were treated with various concentrations of PT1001B or ADMA in the presence of 2.5 ng/ml TGF‐β. We found that treatment with PT1001B increased the deposition of extracellular matrix proteins, the expression of αsmooth muscle actin, and connective tissue growth factor in UUO‐induced fibrotic kidneys, which is correlated with reduced expression of PRMT1, reduced the production of ADMA, and increased expression of uromodulin. In TGF‐β‐stimulated HK2 and NRK‐49F cells, PT1001B dose‐dependently inhibited ADMA production, increased NO concentrations, and enhanced the expression of profibrotic proteins. Exogenous addition of ADMA inhibited the expression of profibrotic proteins dose‐dependently and attenuated the profibrotic effect of PT1001B. Moreover, ADMA reduced the NO concentration in PT1001B‐treated HK2 cells. Finally, we conclude that ADMA has an antifibrotic effect in obstructed kidneys, and future application of type I PRMT inhibitor should be done cautiously for patients with CKD.—Wu, M., Lin, P., Li, L., Chen, D., Yang, X., Xu, L., Zhou, B., Wang, C., Zhang, Y., Luo, C., Ye, C. Reduced asymmetric dimethylarginine accumulation through inhibition of the type I protein arginine methyltransferases promotes renal fibrosis in obstructed kidneys. FASEB J. 33, 6948–6956 (2019). http://www.fasebj.org

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“…Our data further suggest that CCKR signaling may also play a regulatory role in other CKDs. Other enriched signaling pathways in diseased tubules include the apoptosis, TGF-β, MAPK, TNF, integrin, and PI3K-Akt signaling pathways, which have been well studied in the context of CKD [34, 35]. Renal interstitial fibrosis is regarded as a common pathological pathway in CKD.…”

Section: Discussionmentioning

confidence: 99%

Integrative Bioinformatics Analysis Provides Insight into the Molecular Mechanisms of Chronic Kidney Disease

Zhou

Qiu

et al. 2018

Kidney Blood Press Res

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Background/Aims: Chronic kidney disease (CKD) is a worldwide public health problem. Regardless of the underlying primary disease, CKD tends to progress to end-stage kidney disease, resulting in unsatisfactory and costly treatment. Its common pathogenesis, however, remains unclear. The aim of this study was to provide an unbiased catalog of common gene-expression changes of CKD and reveal the underlying molecular mechanism using an integrative bioinformatics approach. Methods: We systematically collected over 250 Affymetrix microarray datasets from the glomerular and tubulointerstitial compartments of healthy renal tissues and those with various types of established CKD (diabetic kidney disease, hypertensive nephropathy, and glomerular nephropathy). Then, using stringent bioinformatics analysis, shared differentially expressed genes (DEGs) of CKD were obtained. These shared DEGs were further analyzed by the gene ontology (GO) and pathway enrichment analysis. Finally, the protein-protein interaction networks(PINs) were constructed to further refine our results. Results: Our analysis identified 176 and 50 shared DEGs in diseased glomeruli and tubules, respectively, including many transcripts that have not been previously reported to be involved in kidney disease. Enrichment analysis also showed that the glomerular and tubulointerstitial compartments underwent a wide range of unique pathological changes during chronic injury. As revealed by the GO enrichment analysis, shared DEGs in glomeruli were significantly enriched in exosomes. By constructing PINs, we identified several hub genes (e.g. OAS1, JUN, and FOS) and clusters that might play key roles in regulating the development of CKD. Conclusion: Our study not only further reveals the unifying molecular mechanism of CKD pathogenesis but also provides a valuable resource of potential biomarkers and therapeutic targets.

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Progression of chronic kidney disease: too much cellular talk causes damage

Cited by 113 publications

References 104 publications

Comprehensive transcriptome analysis of fluid shear stress altered gene expression in renal epithelial cells

Comprehensive transcriptome analysis of fluid shear stress altered gene expression in renal epithelial cells

Reduced asymmetric dimethylarginine accumulation through inhibition of the type I protein arginine methyltransferases promotes renal fibrosis in obstructed kidneys

Integrative Bioinformatics Analysis Provides Insight into the Molecular Mechanisms of Chronic Kidney Disease

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