High glucose-induced fibronectin upregulation in cultured mesangial cells involves caveolin-1-dependent RhoA-GTP activation via Src kinase

Lu,Yongfu; Tang,Lihong; Li,Yiqiao; He,Qiang

doi:10.3892/mmr.2016.5312

High glucose-induced fibronectin upregulation in cultured mesangial cells involves caveolin-1-dependent RhoA-GTP activation via Src kinase

Authors:
- Yongfu Lu
- Lihong Tang
- Yiqiao Li
- Qiang He
View Affiliations

Affiliations: Department of Pathology, Zhejiang University School of Medicine, the First Affiliated Hospital, Hangzhou, Zhejiang 310003, P.R. China, Department of Clinical Laboratory, Hangzhou First People's Hospital, Hangzhou, Zhejiang 310003, P.R. China, Department of Nephrology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China
Published online on: May 19, 2016 https://doi.org/10.3892/mmr.2016.5312
Pages: 963-968

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Zou X, Zhang XX, Liu XY, Li R, Wang M, Wu WJ, Sui Y and Zhao HL: Renal kallikrein activation and renoprotection after dual blockade of renin-angiotensin system in diet-induced diabetic nephropathy. J Diabetes Res. 2015:3106452015. View Article : Google Scholar : PubMed/NCBI
2	Lo CS, Chang SY, Chenier I, Filep JG, Ingelfinger JR, Zhang SL and Chan JS: Heterogeneous nuclear ribonucleoprotein F suppresses angiotensinogen gene expression and attenuates hypertension and kidney injury in diabetic mice. Diabetes. 61:2597–2608. 2012. View Article : Google Scholar : PubMed/NCBI
3	Wu SZ, Peng FF, Li JL, Ye F, Lei SQ and Zhang BF: Akt and RhoA activation in response to high glucose require caveolin-1 phosphorylation in mesangial cells. Am J Physiol Renal. 306:F1308–F1317. 2014. View Article : Google Scholar
4	Xie X, Peng J, Chang X, Huang K, Huang J, Wang S, Shen X, Liu P and Huang H: Activation of RhoA/ROCK regulates NF-κB signaling pathway in experimental diabetic nephropathy. Mol Cell Endocrinol. 369:86–97. 2013. View Article : Google Scholar : PubMed/NCBI
5	Mao Y and Finnemann SC: Regulation of phagocytosis by Rho GTPases. Small GTPases. 6:88–99. 2015. View Article : Google Scholar
6	Perry NA, Vitolo MI, Martin SS and Kontrogianni-Konstantopoulos A: Loss of the obscurin-RhoGEF downregulates RhoA signaling and increases microtentacle formation and attachment of breast epithelial cells. Oncotarget. 5:8558–8568. 2014. View Article : Google Scholar : PubMed/NCBI
7	Kawamura S, Miyamoto S and Brown JH: Initiation and transduction of stretch-induced RhoA and Rac1 activation through caveolae: Cytoskeletal regulation of ERK translocation. J Biol Chem. 278:31111–31117. 2003. View Article : Google Scholar : PubMed/NCBI
8	Peng F, Wu D, Ingram AJ, Zhang B, Gao B and Krepinsky JC: RhoA activation in mesangial cells by mechanical strain depends on caveolae and caveolin-1 interaction. J Am Soc Nephrol. 18:189–198. 2007. View Article : Google Scholar
9	Stary CM, Tsutsumi YM, Patel PM, Head BP, Patel HH and Roth DM: Caveolins: Targeting pro-survival signaling in the heart and brain. Front Physiol. 3:3932012. View Article : Google Scholar : PubMed/NCBI
10	Shankar J, Boscher C and Nabi IR: Caveolin-1, galectin-3 and lipid raft domains in cancer cell signalling. Essays Biochem. 57:189–201. 2015. View Article : Google Scholar : PubMed/NCBI
11	Kang JW and Lee SM: Impaired expression of caveolin-1 contributes to hepatic ischemia and reperfusion injury. Biochem Biophys Res Commun. 450:1351–1357. 2014. View Article : Google Scholar : PubMed/NCBI
12	Balteau M, Van Steenbergen A, Timmermans AD, Dessy C, Behets-Wydemans G, Tajeddine N, Castanares-Zapatero D, Gilon P, Vanoverschelde JL, Horman S, et al: AMPK activation by glucagon-like peptide-1 prevents NADPH oxidase activation induced by hyperglycemia in adult cardiomyocytes. Am J Physiol Circ Physiol. 307:H1120–H1133. 2014. View Article : Google Scholar
13	Wu T, Zhang B, Ye F and Xiao Z: A potential role for caveolin-1 in VEGF-induced fibronectin upregulation in mesangial cells: Involvement of VEGFR2 and Src. Am J Physiol Renal Physiol. 304:F820–F830. 2013. View Article : Google Scholar
14	Zhang Y, Peng F, Gao B, Ingram AJ and Krepinsky JC: High glucose-induced RhoA activation requires caveolae and PKCβ1-mediated ROS generation. Am J Physiol Renal Physiol. 302:F159–F172. 2012. View Article : Google Scholar
15	Jansen M, Pietiainen VM, Polonen H, Rasilainen L, Koivusalo M, Ruotsalainen U, Jokitalo E and Ikonen E: Cholesterol substitution increases the structural heterogeneity of caveolae. J Biol Chem. 283:14610–14618. 2008. View Article : Google Scholar : PubMed/NCBI
16	Radeva G, Perabo J and Sharom FJ: P-Glycoprotein is localized in intermediate-density membrane microdomains distinct from classical lipid rafts and caveolar domains. FEBS J. 272:4924–4937. 2005. View Article : Google Scholar : PubMed/NCBI
17	Karlsson M, Thorn H, Danielsson A, Stenkula KG, Ost A, Gustavsson J, Nystrom FH and Stralfors P: Colocalization of insulin receptor and insulin receptor substrate-1 to caveolae in primary human adipocytes. Cholesterol depletion blocks insulin signalling for metabolic and mitogenic control. Eur J Biochem. 271:2471–2479. 2004. View Article : Google Scholar : PubMed/NCBI
18	Jiao H, Zhang Y, Yan Z, Wang ZG, Liu G, Minshall RD, Malik AB and Hu G: Caveolin-1 Tyr14 phosphorylation induces interaction with TLR4 in endothelial cells and mediates MyD88-dependent signaling and sepsis-induced lung inflammation. J Immunol. 191:6191–6199. 2013. View Article : Google Scholar : PubMed/NCBI
19	Lee H, Volonte D, Galbiati F, Iyengar P, Lublin DM, Bregman DB, Wilson MT, Campos-Gonzalez Boumediene Bouzahza R, Pestell RG, Scherer PE and Lisanti MP: Constitutive and growth factor-regulated phosphorylation of caveolin-1 occurs at the same site (Tyr-14) in vivo: identification of a c-Src/Cav-1/Grb7 signaling cassette. Mol Endocrinol. 14:1750–1775. 2000. View Article : Google Scholar : PubMed/NCBI
20	Lee SH, Lee YJ, Park SW, Kim HS and Han HJ: Caveolin-1 and integrin beta1 regulate embryonic stem cell proliferation via p38 MAPK and FAK in high glucose. J Cell Physiol. 226:1850–1859. 2011. View Article : Google Scholar : PubMed/NCBI
21	Park JH and Ryu JM: Role of FAK, RhoA, PI3K/Akt, and ERK 1/2 pathways. J Cell Physiol. 226:267–275. 2011. View Article : Google Scholar