Faculty Collaboration Database

In vivo selective inhibition of TRPC6 by antagonist BI 749327 ameliorates fibrosis and dysfunction in cardiac and renal disease. Proc Natl Acad Sci U S A 2019 May 14;116(20):10156-10161

Date

04/28/2019

Pubmed ID

31028142

Pubmed Central ID

PMC6525474

DOI

10.1073/pnas.1815354116

Scopus ID

2-s2.0-85065721210 (requires institutional sign-in at Scopus site)   87 Citations

Abstract

Transient receptor potential canonical type 6 (TRPC6) is a nonselective receptor-operated cation channel that regulates reactive fibrosis and growth signaling. Increased TRPC6 activity from enhanced gene expression or gain-of-function mutations contribute to cardiac and/or renal disease. Despite evidence supporting a pathophysiological role, no orally bioavailable selective TRPC6 inhibitor has yet been developed and tested in vivo in disease models. Here, we report an orally bioavailable TRPC6 antagonist (BI 749327; IC₅₀ 13 nM against mouse TRPC6, t_1/2 8.5-13.5 hours) with 85- and 42-fold selectivity over the most closely related channels, TRPC3 and TRPC7. TRPC6 calcium conductance results in the stimulation of nuclear factor of activated T cells (NFAT) that triggers pathological cardiac and renal fibrosis and disease. BI 749327 suppresses NFAT activation in HEK293T cells expressing wild-type or gain-of-function TRPC6 mutants (P112Q, M132T, R175Q, R895C, and R895L) and blocks associated signaling and expression of prohypertrophic genes in isolated myocytes. In vivo, BI 749327 (30 mg/kg/day, yielding unbound trough plasma concentration ∼180 nM) improves left heart function, reduces volume/mass ratio, and blunts expression of profibrotic genes and interstitial fibrosis in mice subjected to sustained pressure overload. Additionally, BI 749327 dose dependently reduces renal fibrosis and associated gene expression in mice with unilateral ureteral obstruction. These results provide in vivo evidence of therapeutic efficacy for a selective pharmacological TRPC6 inhibitor with oral bioavailability and suitable pharmacokinetics to ameliorate cardiac and renal stress-induced disease with fibrosis.

Author List

Lin BL, Matera D, Doerner JF, Zheng N, Del Camino D, Mishra S, Bian H, Zeveleva S, Zhen X, Blair NT, Chong JA, Hessler DP, Bedja D, Zhu G, Muller GK, Ranek MJ, Pantages L, McFarland M, Netherton MR, Berry A, Wong D, Rast G, Qian HS, Weldon SM, Kuo JJ, Sauer A, Sarko C, Moran MM, Kass DA, Pullen SS

Author

Brian L. Lin PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cardiomegaly
Drug Evaluation, Preclinical
Fibrosis
HEK293 Cells
Heart
Humans
Kidney
Mice
Nephrosclerosis
TRPC6 Cation Channel