At the early stage of diabetes, the GFR becomes supernormal. This early hemodynamic phenotype provokes the subsequent demise of a diabetic kidney. The diabetic hyperfiltration is derived from a combined decreased responsiveness of both the renal afferent arterioles and the MCs to vasoconstrictors. Reduced Ca2+ influx is a critical contributing factor to the hypocontractility of MCs in diabetes. However, the underlying mechanism(s) are still poorly understood. Furthermore, emerging evidence implicates NADPH oxidases-, particularly Nox4-derived ROS in the development of diabetic nephropathy. However, the underlying mechanism and downstream signaling pathway are at a large extent unknown. This proposal seeks to test the hypothesis that TRPC6 protein, a newly found Ca2+ permeable channel protein, contributes to the contractile function of MCs and downregulation of the protein in MCs by NADPH oxidases-mediated ROS results in diabetic hyperfiltration.
Three specific aims will be tested. (1) Determine whether TRPC6 regulates contractile function and Ca2+ signaling of glomerular MCs in in vitro, ex vivo, and in vivo systems. (2) Explore the postulate that ROS mediate downregulation of TRPC6 protein expression in glomerular MCs by diabetes in an in vitro (cultured MCs) and in vivo animal model. (3) Determine the source of ROS, focusing on NADPH oxidases, and the molecules downstream ROS, focusing on NF-?B, in the signaling pathway of TRPC6 downregulation by diabetes. The information obtained from this novel study will advance our current understanding of the molecular mechanism for the development of diabetic nephropathy, and therefore provides a rationale for drug design and clinical treatment of diabetes by intervening in the proposed pathway. In addition, TRPC6 has been found to play an important role in a variety of cell types. However, regulation of TRPC6 channel, particularly at gene transcriptional level, is unknown currently. The proposed studies will tackle this important issue by investigating if ROS repress TRPC6 gene transcription through the NF-?B mechanism. Thus, this project is of interest to both ROS and TRPC6 fields.
The proposed study is to test the hypothesis that a decrease in expression level of TRPC6 channel protein leads to the diabetic hyperfiltration at early stage of Diabetes. We further propose that a reactive oxygen species-involved signaling pathway mediates the decrease in TRPC6 protein in diabetes.
|Li, Weizu; Ding, Yanfeng; Smedley, Crystal et al. (2017) Increased glomerular filtration rate and impaired contractile function of mesangial cells in TRPC6 knockout mice. Sci Rep 7:4145|
|Wu, Peiwen; Ren, Yuezhong; Ma, Yuhong et al. (2017) Negative regulation of Smad1 pathway and collagen IV expression by store-operated Ca2+ entry in glomerular mesangial cells. Am J Physiol Renal Physiol 312:F1090-F1100|
|Chaudhari, Sarika; Li, Weizu; Wang, Yanxia et al. (2017) Store-operated calcium entry suppressed the TGF-?1/Smad3 signaling pathway in glomerular mesangial cells. Am J Physiol Renal Physiol 313:F729-F739|
|Chaudhari, Sarika; Ma, Rong (2016) Store-operated calcium entry and diabetic complications. Exp Biol Med (Maywood) 241:343-52|
|Zuckerman, Jonathan E; Gale, Aaron; Wu, Peiwen et al. (2015) siRNA delivery to the glomerular mesangium using polycationic cyclodextrin nanoparticles containing siRNA. Nucleic Acid Ther 25:53-64|
|Wu, Peiwen; Wang, Yanxia; Davis, Mark E et al. (2015) Store-Operated Ca2+ Channels in Mesangial Cells Inhibit Matrix Protein Expression. J Am Soc Nephrol 26:2691-702|
|Wang, Yanxia; Chaudhari, Sarika; Ren, Yuezhong et al. (2015) Impairment of hepatic nuclear factor-4? binding to the Stim1 promoter contributes to high glucose-induced upregulation of STIM1 expression in glomerular mesangial cells. Am J Physiol Renal Physiol 308:F1135-45|
|Ilatovskaya, Daria V; Palygin, Oleg; Chubinskiy-Nadezhdin, Vladislav et al. (2014) Angiotensin II has acute effects on TRPC6 channels in podocytes of freshly isolated glomeruli. Kidney Int 86:506-14|
|Chaudhari, Sarika; Wu, Peiwen; Wang, Yanxia et al. (2014) High glucose and diabetes enhanced store-operated Ca(2+) entry and increased expression of its signaling proteins in mesangial cells. Am J Physiol Renal Physiol 306:F1069-80|
|Ding, Yanfeng; Stidham, Rhesa D; Bumeister, Ron et al. (2013) The synthetic triterpenoid, RTA 405, increases the glomerular filtration rate and reduces angiotensin II-induced contraction of glomerular mesangial cells. Kidney Int 83:845-54|
Showing the most recent 10 out of 18 publications