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TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function

Nature Genetics volume 37, pages 739–744 (2005)Cite this article

Abstract

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.

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Figure 1: TRPC6 expression in the kidney glomerulus.
Figure 2: TRPC6 colocalizes and directly interacts with slit diaphragm proteins.
Figure 3: TRPC6 is upregulated in glomeruli of 2-d-old nephrin-deficient mice, as shown by fluorescence microscopy.
Figure 4: Pedigrees of families with inherited FSGS.
Figure 5: Electrophysiological analysis of mutant TRPC6 channels.

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Acknowledgements

We thank the family members for their participation in these studies and M.A. Arnaout for discussions about the manuscript. This work was supported by grants from the US National Institutes of Health (M.R.P., P.M. and R.K.) as well as the Howard Hughes Medical Institute (P.L.S. and D.E.C.). J.R. was supported by the KMD Foundation and the KUFA-ASN Research Grant.

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Authors and Affiliations

  1. Department of Medicine, Renal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, 02129, Massachusetts, USA

    Jochen Reiser, Clemens C Möller, Mehmet M Altintas & Changli Wei

  2. Renal Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115, Massachusetts, USA

    Krishna R Polu, Peter Kenlan, Stephanie Herbert & Martin R Pollak

  3. Department of Medicine, Mount Sinai School of Medicine, New York, 10029, New York, USA

    Christian Faul & Peter Mundel

  4. Renal Unit, Instituto del Riñon-Fresenius Medical Care, Colombia

    Ivan Villegas

  5. Department of Pathology, Instituto Nacional de Cardiologia Ignacio Chavez, Mexico, 14080, D.F., Mexico

    Carmen Avila-Casado

  6. Program in Membrane Biology and Renal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, 02129, Massachusetts, USA

    Mary McGee & Dennis Brown

  7. Department of Medicine, Center for Matrix Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, 02115, Massachusetts, USA

    Hikaru Sugimoto & Raghu Kalluri

  8. Department of Cardiology, Howard Hughes Medical Institute, Children's Hospital, Boston, 02115, Massachusetts, USA

    Paula L Smith & David E Clapham

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  1. Jochen Reiser
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Corresponding authors

Correspondence to Jochen Reiser or Martin R Pollak.

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Supplementary information

Supplementary Fig. 1

Summary of TRPC6 mutations. (PDF 99 kb)

Supplementary Table 1

Primer sequences. (PDF 43 kb)

Supplementary Note

Clinical information. (PDF 40 kb)

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Reiser, J., Polu, K., Möller, C. et al. TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet 37, 739–744 (2005). https://doi.org/10.1038/ng1592

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