Effects of caveolin-1 and P-ERK1/2 on Ang II-induced glomerular mesangial cell proliferation

Abstract

This study explored the effects of caveolin-1, p-ERK1/2 and transient receptor potential channel 6 (TRPC6) on angiotensin II (Ang II)-induced glomerular mesangial cell (GMC) proliferation, and investigated the role of Ang II on GMC proliferation. GMC cultures were divided into Control, Ang II (Ang II 10 À7 mol/L), PD98059 (Ang II 10 À7 mol/L þ PD98059 5 Â 10 À5 mol/L) and MbCD groups (Ang II 10 À7 mol/L þ MbCD 10 À2 mol/L). GMCs proliferation was measured by the methyl thiazolil tetracolium and trypan blue assays. The distribution of caveolin-1, p-ERK1/2 and TRPC6 was monitored by immunocytochemistry. Real time polymerase chain reaction (PCR) was used to assess mRNA expression of caveolin-1 and TRPC6. Western blot analysis was used to assess protein expression of caveolin-1, p-ERK1/2 and TRPC6. The results showed that Ang II promoted GMC proliferation. PD98059 and MbCD blocked Ang II-induced GMC proliferation, by 31.06% and 48.96%, respectively. In comparison with the control group, the expression of p-ERK1/2 and TRPC6 was significantly higher and caveolin-1 expression was significantly lower in the Ang II group. PD98059 markedly decreased p-ERK1/2 and TRPC6 expression and increased caveolin-1 expression. MbCD decreased the expression of p-ERK1/2 and TRPC6, but had no significant effect on caveolin-1 protein expression. These findings suggested that the intact caveolae structure was associated with Ang II-induced GMC proliferation, ERK1/2 activation and TRPC6 expression. And p-ERK1/2 acted as an upstream signal molecule for TRPC6. Moreover, p-ERK1/2 and caveolin-1 appeared to be inhibited reciprocally, thus regulated GMC proliferation by regulating TRPC6 expression.

Canonical Transient Receptor Potential 6 Channel: A New Target of Reactive Oxygen Species in Renal Physiology and Pathology

“…Expression of TRPC6 protein in human MCs was also reported by several other groups (87,110,119,131,158,233 Diabetic nephropathy is a major and devastating complication of diabetes. At the very onset of diabetes, a dominant pathophysiological characteristic is the development of renal glomerular hyperfiltration (13,214).…”

“…This high-glucose/diabetes-induced decrease in TRPC6 protein expression was MC specific because this response was not observed in the aorta and the heart tissue isolated from those diabetic rats (72) and in high-glucose-treated podocytes (71). Since our study was conducted in rats only 2 weeks after STZ injection, the decrease in abundance of TRPC6 (158,233). In addition, TRPC6 also contributed to phenylephrine (a1-adrenergic receptor agonist)-induced MC proliferation (110).…”

“…In addition, TRPC6 also contributed to phenylephrine (a1-adrenergic receptor agonist)-induced MC proliferation (110). Interestingly, the ERK signaling pathway can work as a mechanism both upstream (in Ang II signaling pathway) (233) and downstream (in a1-adrenergic receptor signaling pathway) (110) TRPC6 expression. Excessive proliferation of MCs is a characteristic pathological feature of glomerulosclerosis.…”

“…Thus, upregulation of TRPC6 expression might be attributed to an ROS independent mechanism. Indeed, Ang II has been shown to increase the TRPC6 protein expression level in MCs (158,233).…”

Therapeutic Effects of FK506 on IgA Nephropathy Rat

“…Another study by Zhuang et al also demonstrated that the inhibition of ERK1/2 signaling via U0126 could markedly block uric acid induced rat mesangial cell proliferation [28]. Similar results were also found in an Ang II-induced glomerular mesangial cell (GMC) proliferation study, and the results revealed that p-ERK1/2 acted as an upstream signaling molecule for TRPC6 [29]. Another study showed that FK506 could activate the ERK1/2 signaling cascade in rat renal mesangial cells [30].…”