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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK079968-04
Application #
8291905
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Rys-Sikora, Krystyna E
Project Start
2009-05-15
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$280,352
Indirect Cost
$72,896
Name
University of North Texas
Department
Physiology
Type
Other Domestic Higher Education
DUNS #
110091808
City
Fort Worth
State
TX
Country
United States
Zip Code
76107
Chaudhari, Sarika; Ma, Rong (2016) Store-operated calcium entry and diabetic complications. Exp Biol Med (Maywood) 241:343-52
Wang, Yanxia; Chaudhari, Sarika; Ren, Yuezhong et al. (2015) Impairment of hepatic nuclear factor-4α 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
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
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
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
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
Shen, Bing; Zhu, Jinhang; Zhang, Jin et al. (2013) Attenuated mesangial cell proliferation related to store-operated Ca2+ entry in aged rat: the role of STIM 1 and Orai 1. Age (Dordr) 35:2193-202
Wang, Yanxia; Ding, Min; Chaudhari, Sarika et al. (2013) Nuclear factor κB mediates suppression of canonical transient receptor potential 6 expression by reactive oxygen species and protein kinase C in kidney cells. J Biol Chem 288:12852-65
Graham, Sarabeth; Yuan, Joseph P; Ma, Rong (2012) Canonical transient receptor potential channels in diabetes. Exp Biol Med (Maywood) 237:111-8

Showing the most recent 10 out of 15 publications