Connexin 43 Prevents the Progression of Diabetic Renal Tubulointerstitial Fibrosis by Regulating the SIRT1-HIF-1α Signaling Pathway

2019 ◽  
Author(s):  
Xiaohong Sun ◽  
Kaipeng Huang ◽  
Haiming Xiao ◽  
Zeyuan Lin ◽  
Yan Yang ◽  
...  
Keyword(s):  
Connexin 43 ◽  
Tubulointerstitial Fibrosis ◽  
Renal Tubulointerstitial Fibrosis

scholarly journals Connexin 43 prevents the progression of diabetic renal tubulointerstitial fibrosis by regulating the SIRT1-HIF-1α signaling pathway

2020 ◽  
Vol 134 (13) ◽  
pp. 1573-1592
Author(s):  
Xiaohong Sun ◽  
Kaipeng Huang ◽  
Xiao Haiming ◽  
Zeyuan Lin ◽  
Yan Yang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Connexin 43 ◽  
Epithelial To Mesenchymal Transition ◽  
Hypoxia Inducible Factor ◽  
Pathological Process ◽  
Tubulointerstitial Fibrosis ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Renal Tubulointerstitial Fibrosis ◽  
Renal Tubular

Abstract Hyperglycemia-induced renal epithelial-to-mesenchymal transition (EMT) is a key pathological factor in diabetic renal tubulointerstitial fibrosis (RIF). Our previous studies have shown that connexin 43 (Cx43) activation attenuated the development of diabetic renal fibrosis. However, whether Cx43 regulates the EMT of renal tubular epithelial cells (TECs) and the pathological process of RIF under the diabetic conditions remains to be elucidated. In the present study, we identified that Cx43 protein expression was down-regulated in the kidney tissues of db/db mice as well as in high glucose (HG)-induced NRK-52E cells. Overexpression of Cx43 improved renal function in db/db spontaneous diabetic model mice, increased SIRT1 levels, decreased hypoxia-inducible factor (HIF)-1α expression, and reduced production of EMT markers and extracellular matrix (ECM) components. Additionally, Cx43 overexpression inhibited the EMT process and reduced the expression of ECM components such as fibronectin (FN), Collagen I, and Collagen IV in HG-induced NRK-52E cells, whereas Cx43 deficiency had the opposite effects. Mechanistically, Cx43 in a carboxyl-terminal signal transduction-dependent manner could up-regulate SIRT1 expression and enhance SIRT1-dependent deacetylation of HIF-1α to reduce HIF-1α activity, which eventually ameliorated renal EMT and diabetic RIF. Our study indicates the essential role of Cx43 in regulating renal EMT and diabetic RIF via regulating the SIRT1-HIF-1α signaling pathway and provides an experimental basis for Cx43 as a potential target for diabetic nephropathy (DN).

scholarly journals Calponin Expression in Renal Tubulointerstitial Fibrosis Induced in Rats by Cisplatin

2014 ◽  
Vol 27 (1) ◽  
pp. 97-103 ◽  
Author(s):  
Takahiro Yuasa ◽  
Ryo Yano ◽  
Takeshi Izawa ◽  
Mitsuru Kuwamura ◽  
Jyoji Yamate
Keyword(s):  
Tubulointerstitial Fibrosis ◽  
Renal Tubulointerstitial Fibrosis

Silymarin Regulates Tgf-β1/Smad3 Signaling Pathway and Improves Renal Tubular Interstitial Fibrosis Caused by Obstructive Nephropathy

2021 ◽  
Vol 19 (4) ◽  
pp. 508-513
Author(s):  
Jinhao Wu ◽  
Chao Huang ◽  
Gang Kan ◽  
Hanyu Xiao ◽  
Xiaoping Zhang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Interstitial Fibrosis ◽  
Tubulointerstitial Fibrosis ◽  
Obstructive Nephropathy ◽  
Therapeutic Drugs ◽  
Renal Tubulointerstitial Fibrosis ◽  
Liver And Kidney ◽  
Renal Tubular ◽  
Antioxidant Effects ◽  
Tgf Β1

Obstructive nephropathy often leads to renal tubulointerstitial fibrosis. Understanding of the pathogenesis of renal tubulointerstitial fibrosis caused by obstructive nephropathy is crucial to the development of effective therapeutic drugs to improve the prognosis of the patients. Silymarin, a polyphenolic flavonoid extracted from plants, has been shown to exhibit antiinflammatory and antioxidant effects ameliorating liver and kidney damage. However, the effect of silymarin on renal fibrosis in obstructive nephropathy remains to be explored. In this study, we found silymarin improved interstitial fibrosis and apoptosis induced by TGF-β1 and ameliorated oxidative damage. Our data further confirmed that silymarin regulates the TGF-β1/ Smad3 signaling pathway, and therefore improves renal tubular interstitial fibrosis caused by obstructive nephropathy.

scholarly journals DsbA-L mediated renal tubulointerstitial fibrosis in UUO mice

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Xiaozhou Li ◽  
Jian Pan ◽  
Huiling Li ◽  
Guangdi Li ◽  
Xiangfeng Liu ◽  
...  
Keyword(s):  
Low Dose ◽  
Aristolochic Acid ◽  
Tissue Growth ◽  
Tubulointerstitial Fibrosis ◽  
Obstructive Nephropathy ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Renal Tubulointerstitial Fibrosis ◽  
Proximal Tubular ◽  
Apoptosis And Inflammation

Abstract Recent studies have reported that upregulation of disulfide-bond A oxidoreductase-like protein (DsbA-L) prevented lipid-induced renal injury in diabetic nephropathy (DN). However, the role and regulation of proximal tubular DsbA-L for renal tubulointerstitial fibrosis (TIF) remains unclear. In current study, we found that a proximal tubules-specific DsbA-L knockout mouse (PT-DsbA-L-KO) attenuated UUO-induced TIF, renal cell apoptosis and inflammation. Mechanistically, the DsbA-L interacted with Hsp90 in mitochondria of BUMPT cells which activated the signaling of Smad3 and p53 to produce connective tissue growth factor (CTGF) and then resulted in accumulation of ECM of BUMPT cells and mouse kidney fibroblasts. In addition, the progression of TIF caused by UUO, ischemic/reperfusion (I/R), aristolochic acid, and repeated acute low-dose cisplatin was also alleviated in PT-DsbA-L-KO mice via the activation of Hsp90 /Smad3 and p53/CTGF axis. Finally, the above molecular changes were verified in the kidney biopsies from patients with obstructive nephropathy (Ob). Together, these results suggest that DsbA-L in proximal tubular cells promotes TIF via activation of the Hsp90 /Smad3 and p53/CTGF axis.

scholarly journals Interaction between V-ATPase B2 and (Pro) renin Receptors in Promoting the progression of Renal Tubulointerstitial Fibrosis

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Yun Liu ◽  
Sujun Zuo ◽  
Xiaoyan Li ◽  
Jinjin Fan ◽  
Xueqin Cao ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Smooth Muscle Actin ◽  
Tubulointerstitial Fibrosis ◽  
Dependent Manner ◽  
Tubular Epithelial Cells ◽  
Atpase Inhibitor ◽  
Renal Tubulointerstitial Fibrosis ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
Atpase Subunits

Abstract To investigate the levels of (Pro) renin receptor [(P) RR], α-smooth muscle actin (α-SMA), fibronectin (FN), and vacuolar H+-ATPase (V-ATPase) subunits (B2, E, and c) in rat unilateral ureteral obstruction (UUO) models and rat proximal tubular epithelial cells (NRK-52E) treated with prorenin to elucidate the role of V-ATPase in these processes by activating the (P) RR. UUO significantly upregulated (P) RR, V-ATPase subunits, α-SMA and FN expression in tubulointerstitium or tubular epithelial cells. A marked colocalization of (P) RR and the B2 subunit was also observed. Prorenin treatment upregulated α-SMA, FN, (P) RR, and V-ATPase subunits and activity in NRK52E cell in a dose- and time-dependent manner. The V-ATPase inhibitor bafilomycin A1 partially blocked prorenin-induced (P) RR, FN, and α-SMA expression. Co-immunoprecipitate and immunofluorescence results demonstrated that the V-ATPase B2 subunit bound to the (P) RR, which was upregulated after prorenin stimulation. Either siRNA-mediated (P) RR or B2 subunit knockdown partially reduced V-ATPase activity and attenuated prorenin-induced FN and α-SMA expression. From the data we can assume that activation of (P) RR and V-ATPase may play an important role in tubulointerstitial fibrosis with possible involvement of interaction of V-ATPase B2 subunit and (P)RR.

scholarly journals Effect of Angiotensin II and Small GTPase Ras Signaling Pathway Inhibition on Early Renal Changes in a Murine Model of Obstructive Nephropathy

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Ana B. Rodríguez-Peña ◽  
Isabel Fuentes-Calvo ◽  
Neil G. Docherty ◽  
Miguel Arévalo ◽  
María T. Grande ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Angiotensin Ii ◽  
Kidney Disease ◽  
Akt Signaling ◽  
Small Gtpase ◽  
Tubulointerstitial Fibrosis ◽  
Ras Signaling ◽  
Signaling System ◽  
Ras Activation ◽  
Renal Tubulointerstitial Fibrosis

Tubulointerstitial fibrosis is a major feature of chronic kidney disease. Unilateral ureteral obstruction (UUO) in rodents leads to the development of renal tubulointerstitial fibrosis consistent with histopathological changes observed in advanced chronic kidney disease in humans. The purpose of this study was to assess the effect of inhibiting angiotensin II receptors or Ras activation on early renal fibrotic changes induced by UUO. Animals either received angiotensin II or underwent UUO. UUO animals received either losartan, atorvastatin, and farnesyl transferase inhibitor (FTI) L-744,832, or chaetomellic acid A (ChA). Levels of activated Ras, phospho-ERK1/2, phospho-Akt, fibronectin, andα-smooth muscle actin were subsequently quantified in renal tissue by ELISA, Western blot, and/or immunohistochemistry. Our results demonstrate that administration of angiotensin II induces activation of the small GTPase Ras/Erk/Akt signaling system, suggesting an involvement of angiotensin II in the early obstruction-induced activation of renal Ras. Furthermore, upstream inhibition of Ras signalling by blocking either angiotensin AT1 type receptor or by inhibiting Ras prenylation (atorvastatin, FTI o ChA) reduced the activation of the Ras/Erk/Akt signaling system and decreased the early fibrotic response in the obstructed kidney. This study points out that pharmacological inhibition of Ras activation may hold promise as a future strategy in the prevention of renal fibrosis.

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