Angiotensin II has acute effects on TRPC6 channels in podocytes of freshly isolated glomeruli

Kidney Int. 2014 Sep;86(3):506-14. doi: 10.1038/ki.2014.71. Epub 2014 Mar 19.

Abstract

A key role for podocytes in the pathogenesis of proteinuric renal diseases has been established. Angiotensin II causes depolarization and increased intracellular calcium concentration in podocytes; members of the cation TRPC channels family, particularly TRPC6, are proposed as proteins responsible for calcium flux. Angiotensin II evokes calcium transient through TRPC channels and mutations in the gene encoding the TRPC6 channel result in the development of focal segmental glomerulosclerosis. Here we examined the effects of angiotensin II on intracellular calcium ion levels and endogenous channels in intact podocytes of freshly isolated decapsulated mouse glomeruli. An ion channel with distinct TRPC6 properties was identified in wild-type, but was absent in TRPC6 knockout mice. Single-channel electrophysiological analysis found that angiotensin II acutely activated native TRPC-like channels in both podocytes of freshly isolated glomeruli and TRPC6 channels transiently overexpressed in CHO cells; the effect was mediated by changes in the channel open probability. Angiotensin II evoked intracellular calcium transients in the wild-type podocytes, which was blunted in TRPC6 knockout glomeruli. Pan-TRPC inhibitors gadolinium and SKF 96365 reduced the response in wild-type glomerular epithelial cells, whereas the transient in TRPC6 knockout animals was not affected. Thus, angiotensin II-dependent activation of TRPC6 channels in podocytes may have a significant role in the development of kidney diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / pharmacology*
  • Animals
  • CHO Cells
  • Calcium / metabolism*
  • Calcium Channel Blockers / pharmacology
  • Cricetulus
  • Gadolinium / pharmacology
  • Imidazoles / pharmacology
  • Kidney Glomerulus / drug effects
  • Kidney Glomerulus / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Podocytes / drug effects*
  • Podocytes / metabolism*
  • Receptor, Angiotensin, Type 1 / metabolism
  • TRPC Cation Channels / drug effects*
  • TRPC Cation Channels / genetics
  • TRPC Cation Channels / metabolism*
  • Up-Regulation / drug effects

Substances

  • Calcium Channel Blockers
  • Imidazoles
  • Receptor, Angiotensin, Type 1
  • TRPC Cation Channels
  • Trpc6 protein, mouse
  • Angiotensin II
  • Gadolinium
  • 1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole
  • Calcium