Transient receptor potential channel 6 (trpc6) protects podocytes during complement-Mediated glomerular disease

Andreas D. KistlerA, Geetika Singh, Mehmet M. Altintas, Hao Yu, Isabel C. Fernandez, Changkyu Gu, Cory Wilson, Sandeep Kumar Srivastava, Alexander Dietrich, Katherina Walz, Dontscho Kerjaschki, Phillip Ruiz, Stuart Dryer, Sanja Sever, Amit K. Dinda, Christian H Faul, Jochen Reiser

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Gain-of-function mutations in the calcium channel TRPC6 lead to autosomal dominant focal segmental glomerulosclerosis and podocyte expression of TRPC6 is increased in some acquired human glomerular diseases, particularly in membranous nephropathy. These observations led to the hypothesis that TRPC6 overactivation is deleterious to podocytes through pathological calcium signaling, both in genetic and acquired diseases. Here, we show that the effects of TRPC6 on podocyte function are context-dependent. Overexpression of TRPC6 alone did not directly affect podocyte morphology and cytoskeletal structure. Unexpectedly, however, overexpression of TRPC6 protected podocytes from complement-mediated injury, whereas genetic or pharmacological TRPC6 inactivation increased podocyte susceptibility to complement. Mechanistically, this effect was mediated by Ca2+/calmodulin-dependent protein kinase II (CaMKII) activation. Podocyte-specificTRPC6 transgenic mice showed stronger CaMKII activation, reduced podocyte foot process effacement and reduced levels of proteinuria during nephrotoxic serum nephritis, whereas TRPC6 null mice exhibited reduced CaMKII activation and higher levels of proteinuria compared with wild type littermates. Human membranous nephropathy biopsy samples showed podocyte staining for active CaMKII, which correlated with the degree of TRPC6 expression. Together, these data suggest a dual and context dependent role of TRPC6 in podocytes where acute activation protects from complement-mediated damage, but chronic overactivation eads to focal segmental glomerulosclerosis.

Original languageEnglish
Pages (from-to)36598-36609
Number of pages12
JournalJournal of Biological Chemistry
Volume288
Issue number51
DOIs
StatePublished - Dec 20 2013

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

KistlerA, A. D., Singh, G., Altintas, M. M., Yu, H., Fernandez, I. C., Gu, C., Wilson, C., Srivastava, S. K., Dietrich, A., Walz, K., Kerjaschki, D., Ruiz, P., Dryer, S., Sever, S., Dinda, A. K., Faul, C. H., & Reiser, J. (2013). Transient receptor potential channel 6 (trpc6) protects podocytes during complement-Mediated glomerular disease. Journal of Biological Chemistry, 288(51), 36598-36609. https://doi.org/10.1074/jbc.M113.488122