Canonical Transient Receptor Potential 1 Channel Is Involved in Contractile Function of Glomerular Mesangial Cells

Abstract

Contractility of mesangial cells (MC) is tightly controlled by [G lomerular mesangial cells (MC) are located within glomerular capillary loops and contribute to the physiologic regulation of glomerular hemodynamics (1). Altered responsiveness of MC to hormones is one of the major causes that lead to various renal diseases. Ca 2ϩ influx across the plasma membrane is a major component of MC responses to vasoconstrictors (1). Several types of Ca 2ϩ -conductive channels in the plasma membrane are involved in the physiologic processes. These channels include voltage-operated Ca 2ϩ channel (VOCC), receptor-operated channel (ROC), and recently found store-operated channel (SOC) (1,2). In contrast to the widely known VOCC, the molecular identity, physiologic significance, and regulatory mechanism of ROC and SOC in the glomerular contractile cells remain unknown.Recently, the channel proteins from a new family, canonical transient receptor potential (TRPC), were found in a variety of cells (3). TRPC family includes seven related members, designated as TRPC1 through 7 (3). Pharmacologic and electrophysiologic studies in conjunction with molecular biologic tools and Ca 2ϩ imagings have demonstrated that TRPC channel activity is tightly linked to the signaling cascade of G protein-coupled receptor or receptor tyrosine kinase (4,5), supporting the current hypothesis that TRPC proteins are potential candidates for ROC and SOC. TRPC proteins have been identified in glomeruli and glomerular MC (6 -8). Our previous work also demonstrated that human MC selectively express TRPC1,3,4, and 6 (9). However, the function, regulation, and physiologic relevance of these glomerular TRPC are unexplored at large extent. In this study, we focused on TRPC1 and investigated its contribution to mesangial contraction in vitro and in vivo. Our results indicate that TRPC1 is an important component mediating contractile responses of MC. The TRPC1-involved mesangial contraction is attributed to TRPC1-associated Ca 2ϩ influx. Materials and Methods AnimalsTwo-to 3-mo-old male Sprague-Dawley rats were used in this study. All rats were purchased from Harlan (Indianapolis, IN). Care and use of all animals in this study were in strict agreement with the guidelines set forth by the University of North Texas Health Science Center. Measurement of GFR and Renal Blood FlowGFR and renal blood flow (RBF) were estimated by measurement of inulin and para-aminohippurate (PAH) plasma clearances as described

Impairment of hepatic nuclear factor-4α binding to theStim1promoter contributes to high glucose-induced upregulation of STIM1 expression in glomerular mesangial cells

“…Recently, Niehof and Borlak (32) reported that HNF4␣ protein was significantly reduced in kidneys from diabetic rats and humans. The decrease in HNF4␣ in the diabetic kidney downregulated expression of TRPC1 protein, a Ca 2ϩ channel that regulates Ca 2ϩ signals in kidney cells (10). In the present study, we provide evidence that HNF4␣ can regulate another type of Ca 2ϩ channel, i.e., SOCs, by repressing STIM1 transcription.…”

“…A recent study by Niehof and Borlak (32) showed that HNF4␣ protein expression was repressed in kidneys of both diabetic rats and humans and that the reduced HNF4␣ might contribute to diabetic nephropathy by inhibiting canonical transient receptor potential (TRP)C1 protein in the kidney (32). Since TRPC1 is a Ca 2ϩ -permeable channel expressed in kidney cells (10), the results of Niehof and Borlak's study suggest that HNF4␣ may affect diabetic renal changes by regulating renal cell Ca 2ϩ signaling. STIM1-gated Ca 2ϩ channels participate in the Ca 2ϩ response in glomerular MCs (39,42), and dysfunction of MCs contributes to the progression of diabetic kidney disease.…”

HNF4α and the Ca-Channel TRPC1 Are Novel Disease Candidate Genes in Diabetic Nephropathy

“…We propose TRPC1 to be a disease candidate gene in diabetic nephropathy. Recently, TRPC1 was identified in glomerular mesangial cells (29,30) to contribute to contractile function (31). Essentially, mesangial cells are located within glomerular capillary loops and play a role in the physiological regulation of glomerular hemodynamics and filtration (28,30).…”

Downregulation of TRPC6 protein expression by high glucose, a possible mechanism for the impaired Ca2+signaling in glomerular mesangial cells in diabetes

“…Since human MCs possess multiple isoforms of TRPC channel proteins (36), we inferred that the resting tone of MCs might be the function of those TRPC isoforms or could be mediated by other types of ion channels in the plasma membrane. Indeed, we recently found that the biological knockdown of TRPC1 using an RNAi approach or functional blockade of TRPC1 channel using a specific TRPC1 antibody significantly reduced basal membrane currents in cultured MCs (8).…”