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Diabetes Downregulates TRPC6 Protein Expression in Glomerular Mesangial Cells via a ROS and PKC Pathway
Author(s) -
Graham Sarabeth Marie,
Gorin Yves,
Abboud Hanna,
Ding Min,
Lee Duck Yoon,
Ding Yanfeng,
Pulse Mark,
Ma Rong
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.664.1
Subject(s) - nox4 , protein kinase c , nadph oxidase , gene knockdown , trpc6 , catalase , superoxide dismutase , chemistry , downregulation and upregulation , streptozotocin , medicine , endocrinology , activator (genetics) , reactive oxygen species , oxidative stress , diabetes mellitus , microbiology and biotechnology , signal transduction , biology , biochemistry , apoptosis , receptor , transient receptor potential channel , gene
The present study was performed to investigate the underlying mechanism, particularly focused on the roles of ROS and PKC in diabetes‐induced TRPC6 downregulation. We found that high glucose (HG) significantly reduced TRPC6 protein expression in cultured MCs. TRPC6 protein was also significantly reduced in the glomeruli, but not in the whole heart or aorta isolated from streptozotocin‐induced diabetic rats, suggesting a tissue specific effect of diabetes on TRPC6 protein expression. In the cultured MCs, H2O2 suppressed TRPC6 protein expression in a dose and time dependent manner, which emulated the high glucose effect. Catalase as well as superoxide dismutase were able to prevent the inhibitory effect of HG on TRPC6. The antioxidant effect observed in cultured cells was also observed in diabetic rats treated with tempol for 2 weeks which exhibited a preservation of TRPC6 in the glomeruli. Specific knockdown of Nox4, a component of NADPH oxidase, increased TRPC6 protein expression. Furthermore, the PKC activator, PMA, but not its analog 4α‐PDD, suppressed TRPC6 expression and this PMA effect was not affected by catalase. Moreover, a PKCα and βI inhibitor, Gö6976 attenuated the negative effect of both HG and H2O2 on TRPC6 expression. These results suggest that hyperglycemia in diabetes downregulated TRPC6 protein expression in MCs through a NADPH oxidase Nox4‐ROS‐PKC pathway. (Supported by NIH and ADA)