KATP channels in high glucose-induced rat mesangial cell proliferation and release of MMP-2 and fibronectin

Abstract

ATP-sensitive potassium (KATP) channels are well characterized in cardiac, pancreatic and many other muscle cells. The purpose of this study was to determine if KATP channels play a role in diabetic nephropathy (DN). In the present study, functional expression of the KATP channel was examined in rat mesangial cells with or without high glucose (HG) stimulation. The mesangial cell proliferation and the release of matrix metalloproteinase (MMP)-2 and fibronectin in response to high glucose with a selective opener of KATP (diazoxide, DZX), or with a selective inhibitor of KATP (5-hydroxydecanoate, 5-HD) were also measured. The cell proliferation was observed using Cell Counting Kit-8 assay, and the mRNA expressions of KATP subunit, including Kir6.1, Kir6.2, sulfonylurea receptor 1 (SUR1), SUR2A and SUR2B, were assessed using quantitative real-time PCR. MMP-2 and fibronectin release was measured by ELISA. The present study clarified expression of SUR subunit of KATP in plasma. HG treatment could cause increased cell proliferation and release of MMP-2 and fibronectin in a dose-dependent manner. HG also significantly decreased the expression of Kir6.1, SUR2A and SUR2B. Pretreatment of DZX markedly decreased the expression of SUR1, SUR2A and SUR2B, but had no effect on Kir6.1 expression compared with HG alone, while these changes were inhibited by 5-HD pretreatment. Moreover, DZX also inhibited cell proliferation and release of MMP-2 and fibronectin in HG-induced rat mesangial cells, and that was corrected by 5-HD. These data suggest that HG stimulates mesangial cell proliferation and cellular matrix release via inhibiting KATP channel activity, leading us to propose that KATP channel dysfunction may be involved in the development of DN.

Effect of ATP-sensitive Potassium Channel Openers on Intraocular Pressure in Ocular Hypertensive Animal Models

“…Studies performed in the heart and pancreas have shown that diazoxide can directly affect Erk1/2 phosphorylation and matrix metalloproteinase activity. 40 , 41 The Erk1/2 pathway is a strong modulator of matrix metalloproteinases, which have been shown to be necessary for ECM turnover in the trabecular meshwork and uveoscleral outflow pathway in association with IOP reduction. 42 , 43 Additionally, the K ATP channel opener iptakalim was shown to reduce accumulation of collagen IV and fibronectin in the renal vasculature of a rat hypertension model by inhibiting TGFβ1 expression and normalizing matrix metalloproteinase 9 and TIMP1 function.…”