Renal tubule injury: a driving force toward chronic kidney disease

Liu, Bi-Cheng; Tang, Tao-Tao; Lv, Lin‐Li; Lan, Hui‐Yao

doi:10.1016/j.kint.2017.09.033

Cited by 612 publications

(472 citation statements)

References 217 publications

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“…PAR2 activation in human tubular epithelial cells up‐regulates production of pro‐inflammatory (CCL2 and TNF) and pro‐fibrotic (TGF‐β1, CTGF) molecules, at least in part, via ERK signalling . However, our study demonstrates that PAR2 does not play a significant role in the UUO model in terms of ERK or Akt activation or in the up‐regulation of Ccl2 , Tnf , Tgfb1 and Ctgf mRNA levels which are expressed predominantly by tubular epithelial cells in this model …”

Section: Discussioncontrasting

confidence: 54%

Protease‐activated receptor 2 does not contribute to renal inflammation or fibrosis in the obstructed kidney

et al. 2019

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Aim Protease‐activated receptor 2 (PAR2) has been implicated in the development of renal inflammation and fibrosis. In particular, activation of PAR2 in cultured tubular epithelial cells induces extracellular signal‐regulated kinase signalling and secretion of fibronectin, C–C Motif Chemokine Ligand 2 (CCL2) and transforming growth factor‐β1 (TGF‐β1), suggesting a role in tubulointerstitial inflammation and fibrosis. We tested this hypothesis in unilateral ureteric obstruction (UUO) in which ongoing tubular epithelial cell damage drives tubulointerstitial inflammation and fibrosis. Methods Unilateral ureteric obstruction surgery was performed in groups (n = 9/10) of Par2−/− and wild type (WT) littermate mice which were killed 7 days later. Non‐experimental mice were controls. Results Wild type mice exhibited a 5‐fold increase in Par2 messenger RNA (mRNA) levels in the UUO kidney. In situ hybridization localized Par2 mRNA expression to tubular epithelial cells in normal kidney, with a marked increase in Par2 mRNA expression by tubular cells, including damaged tubular cells, in WT UUO kidney. Tubular damage (tubular dilation, increased KIM‐1 and decreased α‐Klotho expression) and tubular signalling (extracellular signal‐regulated kinase phosphorylation) seen in WT UUO were not altered in Par2−/− UUO. In addition, macrophage infiltration, up‐regulation of M1 (NOS2) and M2 (CD206) macrophage markers, and up‐regulation of pro‐inflammatory molecules (tumour necrosis factor, CCL2, interleukin‐36α) in WT UUO kidney were unchanged in Par2−/− UUO. Finally, the accumulation of α‐SMA+ myofibroblasts, deposition of collagen IV and expression of pro‐fibrotic factors (CTGF, TGF‐β1) were not different between WT and Par2−/− UUO mice. Conclusion Protease‐activated receptor 2 expression is substantially up‐regulated in tubular epithelial cells in the obstructed kidney, but this does not contribute to the development of tubular damage, renal inflammation or fibrosis.

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Section: Discussioncontrasting

confidence: 54%

Protease‐activated receptor 2 does not contribute to renal inflammation or fibrosis in the obstructed kidney

et al. 2019

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“…Direct epithelial damage causes de-differentiation and upregulation of mediators that orchestrate pro-inflammatory signaling 58 and activate interstitial myofibroblasts in a paracrine fashion. Direct epithelial damage causes de-differentiation and upregulation of mediators that orchestrate pro-inflammatory signaling 58 and activate interstitial myofibroblasts in a paracrine fashion.…”

Section: The Protective Role Of Mir-9-5p In Kidney Fibrosis Is Medimentioning

confidence: 99%

MiR‐9‐5p protects from kidney fibrosis by metabolic reprogramming

et al. 2019

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MicroRNAs (miRNAs) regulate gene expression posttranscriptionally and controlbiological processes (BPs), including fibrogenesis. Kidney fibrosis remains a clinical challenge and miRNAs may represent a valid therapeutic avenue. We show that miR-9-5p protected from renal fibrosis in the mouse model of unilateral ureteral obstruction (UUO). This was reflected in reduced expression of pro-fibrotic markers, decreased number of infiltrating monocytes/macrophages, and diminished tubular epithelial cell injury and transforming growth factor-beta 1 (TGF-β1)-dependent dedifferentiation in human kidney proximal tubular (HKC-8) cells. RNA-sequencing (RNA-Seq) studies in the UUO model revealed that treatment with miR-9-5p prevented the downregulation of genes related to key metabolic pathways, including mitochondrial function, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and glycolysis. Studies in human tubular epithelial cells demonstrated that miR-9-5p impeded TGF-β1-induced bioenergetics derangement. The expression of the FAO-related axis peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α)-peroxisome proliferator-activated receptor alpha (PPARα) was reduced by UUO, although preserved by the administration of miR-9-5p. We found that in mice null for the mitochondrial master regulator PGC-1α, miR-9-5p was unable to promote a protective effect in the UUO model. We propose that miR-9-5p elicits a protective response to chronic kidney injury and renal fibrosis by inducing | 411 FIERRO-FERNÁNDEZ Et al.

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“…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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Renal tubule injury: a driving force toward chronic kidney disease

Cited by 612 publications

References 217 publications

Protease‐activated receptor 2 does not contribute to renal inflammation or fibrosis in the obstructed kidney

Protease‐activated receptor 2 does not contribute to renal inflammation or fibrosis in the obstructed kidney

MiR‐9‐5p protects from kidney fibrosis by metabolic reprogramming

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

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