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Gq signaling causes glomerular injury by activating TRPC6.

Publication ,  Journal Article
Wang, L; Jirka, G; Rosenberg, PB; Buckley, AF; Gomez, JA; Fields, TA; Winn, MP; Spurney, RF
Published in: J Clin Invest
May 2015

Familial forms of focal segmental glomerulosclerosis (FSGS) have been linked to gain-of-function mutations in the gene encoding the transient receptor potential channel C6 (TRPC6). GPCRs coupled to Gq signaling activate TRPC6, suggesting that Gq-dependent TRPC6 activation underlies glomerular diseases. Here, we developed a murine model in which a constitutively active Gq α subunit (Gq(Q209L), referred to herein as GqQ>L) is specifically expressed in podocytes and examined the effects of this mutation in response to puromycin aminonucleoside (PAN) nephrosis. We found that compared with control animals, animals expressing GqQ>L exhibited robust albuminuria, structural features of FSGS, and reduced numbers of glomerular podocytes. Gq activation stimulated calcineurin (CN) activity, resulting in CN-dependent upregulation of TRPC6 in murine kidneys. Deletion of TRPC6 in GqQ>L-expressing mice prevented FSGS development and inhibited both tubular damage and podocyte loss induced by PAN nephrosis. Similarly, administration of the CN inhibitor FK506 reduced proteinuria and tubular injury but had more modest effects on glomerular pathology and podocyte numbers in animals with constitutive Gq activation. Moreover, these Gq-dependent effects on podocyte injury were generalizable to diabetic kidney disease, as expression of GqQ>L promoted albuminuria, mesangial expansion, and increased glomerular basement membrane width in diabetic mice. Together, these results suggest that targeting Gq/TRPC6 signaling may have therapeutic benefits for the treatment of glomerular diseases.

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Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

May 2015

Volume

125

Issue

5

Start / End Page

1913 / 1926

Location

United States

Related Subject Headings

  • Tacrolimus
  • TRPC6 Cation Channel
  • TRPC Cation Channels
  • Signal Transduction
  • Recombinant Fusion Proteins
  • Puromycin Aminonucleoside
  • Point Mutation
  • Podocytes
  • NFATC Transcription Factors
  • Mice, Transgenic
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Wang, L., Jirka, G., Rosenberg, P. B., Buckley, A. F., Gomez, J. A., Fields, T. A., … Spurney, R. F. (2015). Gq signaling causes glomerular injury by activating TRPC6. J Clin Invest, 125(5), 1913–1926. https://doi.org/10.1172/JCI76767
Wang, Liming, Grant Jirka, Paul B. Rosenberg, Anne F. Buckley, Jose A. Gomez, Timothy A. Fields, Michelle P. Winn, and Robert F. Spurney. “Gq signaling causes glomerular injury by activating TRPC6.J Clin Invest 125, no. 5 (May 2015): 1913–26. https://doi.org/10.1172/JCI76767.
Wang L, Jirka G, Rosenberg PB, Buckley AF, Gomez JA, Fields TA, et al. Gq signaling causes glomerular injury by activating TRPC6. J Clin Invest. 2015 May;125(5):1913–26.
Wang, Liming, et al. “Gq signaling causes glomerular injury by activating TRPC6.J Clin Invest, vol. 125, no. 5, May 2015, pp. 1913–26. Pubmed, doi:10.1172/JCI76767.
Wang L, Jirka G, Rosenberg PB, Buckley AF, Gomez JA, Fields TA, Winn MP, Spurney RF. Gq signaling causes glomerular injury by activating TRPC6. J Clin Invest. 2015 May;125(5):1913–1926.

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

May 2015

Volume

125

Issue

5

Start / End Page

1913 / 1926

Location

United States

Related Subject Headings

  • Tacrolimus
  • TRPC6 Cation Channel
  • TRPC Cation Channels
  • Signal Transduction
  • Recombinant Fusion Proteins
  • Puromycin Aminonucleoside
  • Point Mutation
  • Podocytes
  • NFATC Transcription Factors
  • Mice, Transgenic