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
04/28/2019Pubmed ID
31028142Pubmed Central ID
PMC6525474DOI
10.1073/pnas.1815354116Scopus ID
2-s2.0-85065721210 (requires institutional sign-in at Scopus site) 93 CitationsAbstract
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, t1/2 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 SSAuthor
Brian L. Lin PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCardiomegaly
Drug Evaluation, Preclinical
Fibrosis
HEK293 Cells
Heart
Humans
Kidney
Mice
Nephrosclerosis
TRPC6 Cation Channel