Reiser, J. et al. TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat. Genet. 37, 739-744

Renal Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129, USA.
Nature Genetics (Impact Factor: 29.35). 08/2005; 37(7):739-44. DOI: 10.1038/ng1592
Source: PubMed


Progressive kidney failure is a genetically and clinically heterogeneous group of disorders. Podocyte foot processes and the interposed glomerular slit diaphragm are essential components of the permeability barrier in the kidney. Mutations in genes encoding structural proteins of the podocyte lead to the development of proteinuria, resulting in progressive kidney failure and focal segmental glomerulosclerosis. Here, we show that the canonical transient receptor potential 6 (TRPC6) ion channel is expressed in podocytes and is a component of the glomerular slit diaphragm. We identified five families with autosomal dominant focal segmental glomerulosclerosis in which disease segregated with mutations in the gene TRPC6 on chromosome 11q. Two of the TRPC6 mutants had increased current amplitudes. These data show that TRPC6 channel activity at the slit diaphragm is essential for proper regulation of podocyte structure and function.

Download full-text


Available from: Mehmet M Altintas,
    • "For this reason and because podocytes were assumed not to be replaceable, ion channels expressed in glomerular podocytes and their foot processes have attracted special attention and it was hypothesized that the identified TRPC6 mutations may cause FSGS by inducing podocyte dysfunction and cell death. Therefore, channel mutants characterized by increased Ca 2þ influx (P112Q, [Winn et al., 2005]) or larger current amplitudes (R895C and E897K, [Reiser et al., 2005]) in a heterologous expression system were expressed in immortalized podocyte cell lines. TRPC6 dependent Ca 2þ influx induced calcineurin activation and synaptopodin dephosphorylation resulting in decreased protection of RhoA, a protein essential for actin polymerization and stress fiber formation, from proteasomal degradation (Faul et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In eukaryotic cells, activation of phospholipase C (PLC)-coupled membrane receptors by hormones leads to an increase in the intracellular Ca(2+) concentration [Ca(2+) ]i . Catalytic activity of PLCs results in the hydrolysis of phosphatidylinositol 4,5-bisphosphate to generate inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) which opens DAG-sensitive classical transient receptor channels 3, 6 and 7 (TRPC3/6/7), initiating Ca(2+) influx from the extracellular space. Patients with focal segmental glomerulosclerosis (FSGS) express gain-of-function mutants of TRPC6, while others carry loss-of-function mutants of PLCε, raising the intriguing possibility that both proteins interact and might work in the same signalling pathway. While TRPC6 activation by PLCβ and PLCγ isozymes was extensively studied, the role of PLCε in TRPC6 activation remains elusive. TRPC6 was co-immunoprecipitated with PLCε in a heterologous overexpression system in HEK293 cells as well as in freshly isolated murine podocytes. Receptor-operated TRPC6 currents in HEK293 cells expressing TRPC6 were reduced by a specific PLCε siRNA and by a PLCε loss-of-function mutant isolated from a patient with FSGS. PLCε-induced TRPC6 activation was also identified in murine embryonic fibroblasts (MEFs) lacking Gαq/11 proteins. Further analysis of the signal transduction pathway revealed a Gα12/13 Rho-GEF activation which induced Rho-mediated PLCε stimulation. Therefore, we identified a new pathway for TRPC6 activation by PLCε. PLCε-/- podocytes however, were undistinguishable from WT podocytes in their angiotensin II-induced formation of actin stress fibers and their GTPγS-induced TRPC6 activation, pointing to a redundant role of PLCε-mediated TRPC6 activation at least in podocytes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Cellular Physiology 06/2015; 230(6). DOI:10.1002/jcp.24883 · 3.84 Impact Factor
  • Source
    • "The transient receptor potential cation channel 6 (trpc6) is a gene located in the long arm of chromosome 11 (11q22.1) encoding a protein of the same name [42, 43]. It is considered to be a receptor-activated nonselective calcium permanent cation channel [103]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Focal segmental glomerulosclerosis (FSGS) is a glomerulopathy associated with nephrotic syndrome and podocyte injury. FSGS occurs both in children and adults and it is considered the main idiopathic nephrotic syndrome nowadays. It is extremely difficult to establish a morphological diagnosis, since some biopsies lack a considerable quantifiable number of sclerotic glomeruli, given their focal aspect and the fact that FSGS occurs in less than half of the glomeruli. Therefore, many biological molecules have been evaluated as potential markers that would enhance the diagnosis of FSGS. Some of these molecules and receptors are associated with the pathogenesis of FSGS and have potential use in diagnosis.
    Disease markers 02/2014; 2014:192836. DOI:10.1155/2014/192836 · 1.56 Impact Factor
  • Source
    • "Transient receptor potential canonical channel 6 (TRPC6) is one of the important Ca2+ permeable ion channels in podocytes, which is a component of the glomerular SD [64]. Mutations in gene encoding TRPC6 have been shown to cause FSGS [65]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Podocytes have a complex cellular architecture with interdigitating processes maintained by a precise organization of actin filaments. The actin-based foot processes of podocytes and the interposed slit diaphragm form the final barrier to proteinuria. The function of podocytes is largely based on the maintenance of the normal foot process structure with actin cytoskeleton. Cytoskeletal dynamics play important roles during normal podocyte development, in maintenance of the healthy glomerular filtration barrier, and in the pathogenesis of glomerular diseases. In this review, we focused on recent findings on the mechanisms of organization and reorganization of these actin-related molecules in the pathogenesis of podocyte injury and potential therapeutics targeting the regulation of actin cytoskeleton in podocytopathies.
    Current Genomics 11/2013; 14(7):477-84. DOI:10.2174/13892029113146660014 · 2.34 Impact Factor
Show more