title: High glucose-induced fibronectin upregulation in cultured mesangial cells involves caveolin-1-dependent RhoA-GTP activation via Src kinase.
abstract: Increasing evidence indicates that diabetes-mediated renal interstitial fibrosis through extracellular matrix (ECM) protein accumulation is an important event in the development of diabetic kidney disease (DKD), however, the underlying mechanism remains unclear. In the current study, it was observed that high levels of glucose (HG) time‑ and dose-dependently increased the production of the ECM protein, fibronectin (FN), in primary rat mesangial cells. Inhibition of the Rho pathway blocked HG‑induced FN upregulation. HG‑induced RhoA activation was prevented by inhibiting caveolae with filipin III or caveolin‑1 siRNA and rescued by exogenous caveolin‑1. HG also increased caveolin-1/Src association and activated Src kinase, whereas the inhibition of Src blocked RhoA activation and FN upregulation. Src-mediated phosphorylation of caveolin‑1 on Y14 has also been implicated in signaling responses. Overexpression of the nonphosphorylatable caveolin‑1 Y14A mutant prevented the HG‑induced RhoA activation and FN upregulation. In conclusion, HG‑induced FN upregulation requires caveolae and caveolin‑1 to interact with RhoA and Src kinases. Interference with Src/caveolin-1/RhoA signaling may provide novel mechanistic targets for the treatment of DKD.
authors.affiliation: Department of Pathology, Zhejiang University School of Medicine, the First Affiliated Hospital, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Yongfu
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Clinical Laboratory, Hangzhou First People's Hospital, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Lihong
authors.initials: L
authors.lastname: Tang
authors.affiliation: Department of Nephrology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China.
authors.forename: Yiqiao
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Nephrology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: He
mesh_terms: D000818:Animals; D001786:Blood Glucose; D021941:Caveolae / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism*; D002478:Cells, Cultured; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D005353:Fibronectins / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D015854:Up-Regulation; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D051242:Caveolin 1; D005353:Fibronectins; D019061:src-Family Kinases; D020742:rhoA GTP-Binding Protein; D005947:Glucose