PTEN improve renal fibrosis in vitro and in vivo through inhibiting FAK/AKT signaling pathway

Abstract

Renal fibrosis, the ultimate common pathway of progressive nephropathy, is characterized by excess accumulation and deposition of extracellular matrix (ECM) within the renal interstitium and glomeruli, finally resulting in end‐stage kidney failure. TGFβ1 is not only abnormally increased during fibrosis but also involved in ECM induction and accumulation. Based on the bioinformative analyses, phosphatase and tensin homolog deleted on chromosome ten (PTEN) and focal adhesion kinase (FAK) signaling pathway might be involved in TGFβ1 functions on renal fibrosis development. In the present study, fibrosis was induced in HK‐2 cells using TGFβ1 and PTEN expression was significantly suppressed by 24 or 48 hours TGFβ1 treatment. PTEN overexpression in HK‐2 cells improved TGFβ1‐induced fibrosis within α‐SMA and E‐cadherin. According to the KEGG signaling pathway annotation analyses on microarray profiles (GSE23338 and GSE20247) and immunoblotting validation, FAK signaling might be involved in PTEN functions in TGFβ1‐induced fibrosis. PTEN overexpression significantly inhibited TGFβ1‐ or unilateral ureteral obstruction (UUO)‐induced FAK signaling pathway activation both in vitro and in vivo; more importantly, PTEN silence enhanced TGFβ1‐ or UUO‐induced fibrosis, while FAK inhibitor PF567721 significantly reversed the effects of PTEN silence, indicating that PTEN exerted its effects on TGFβ1‐ and UUO‐induced fibrotic development in vitro and in vivo via inhibiting FAK signaling pathway. In summary, these findings indicate that PTEN could improve cellular fibrotic changes and renal fibrosis via inhibiting FAK/AKT signaling pathway. Restoring PTEN expression to target FAK/AKT signaling pathway might be a potent strategy for renal fibrosis treatment.

Upregulation of miR-382 contributes to renal fibrosis secondary to aristolochic acid-induced kidney injury via PTEN signaling pathway

“…In addition, our study demonstrated that the loss of PTEN expression in renal fibrosis, which has since been substantiated by many recent studies 14,18,41,42 . Both in vivo and in vitro, phosphorylation of AKT on Ser473 was increased as along with AA-induced kidney injury, which was consistent with previous studies 43 .…”

“…Phosphatase and tensin homologs deleted on chromosome 10 (PTEN)/protein kinase B(AKT) pathway has been reported in tumors as a tumor suppressor 16,17 . In addition, depletion of PTEN was characteristic of renal fibrosis and overexpression of PTEN expression attenuated tubulointerstitial fibrosis [18][19][20][21][22] , inhibited macrophage polarization from M1 to M2 23,24 and suppressed inflammation responses 25,26 . Given that PTEN has been identified as a target of miR-382 in liver generation, acute promyelocytic leukemia, and tumor angiogenesis as well as oxidative stress of the tubular epithelium [27][28][29][30] , which remains unclear in kidney fibrosis.…”

miR-301a-PTEN-AKT Signaling Induces Cardiomyocyte Proliferation and Promotes Cardiac Repair Post-MI

“… 45 , 46 The focal adhesion kinase (FAK) pathway, the mitogen-activated protein kinase (MAPK) pathway, and the PI3K/AKT pathway have been demonstrated to be downstream signaling of PTEN. 47 , 48 , 49 Mostly PTEN dephosphorylates PIP3 (phosphatidylinositol (3,4,5)-trisphosphate) to PIP2 (phosphatidylinositol (4,5)-bisphosphate), thereby arresting the cell cycle at the G 1 phase through the PI3K/AKT pathway, 49 which has been reported to be involved in a wide variety of cardiovascular diseases, regulating survival, proliferation, apoptosis, hypertrophy, and contractility of cardiac cells. 50 In the current study, PTEN was identified as a target gene of miR-301a in cardiomyocytes.…”

Focusing on Mechanoregulation Axis in Fibrosis: Sensing, Transduction and Effecting

“…Silencing PTEN enhances fibrosis, which can be significantly reversed by the FAK inhibitor PF567721. These findings suggest that PTEN can promote renal fibrosis through the FAK/AKT signaling pathway ( Du et al, 2019 ).…”