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广东快乐十分助赢计划:In vivo selective inhibition of TRPC6 by antagonist BI 749327 ameliorates fibrosis and dysfunction in cardiac and renal disease
广东快乐十分投注下载 www.hmclip.net Edited by Christine E. Seidman, Howard Hughes Medical Institute, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, and approved March 28, 2019 (received for review September 7, 2018)
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Transient receptor potential canonical 6 (TRPC6) is an important mediator of pathological hypertrophy and fibrosis, contributing to renal and cardiac disease. However, no selective TRPC6 inhibitor with in vivo efficacy has been developed and tested to determine if nongenetic channel suppression ameliorates disease in intact animals. We developed and tested an orally bioavailable TRPC6-specific inhibitor, BI 749327, revealing its capacity to improve cardiac function and reduce chamber dilation and fibrosis in the context of abnormal hemodynamic stress. Similarly, BI 749327 suppressed myofibroblast activation and fibrosis in a renal disease model. These data support BI 749327 as a representative of a therapeutic class for treating cardiac and renal disease and provide a tool for studying the biological function of TRPC6.
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.
- ?1To whom correspondence may be addressed. Email: or .
Author contributions: B.L.L., D.M., J.F.D., D.d.C., D.W., J.J.K., A.S., C.S., M.M.M., D.A.K., and S.S.P. designed research; B.L.L., D.M., J.F.D., N.Z., D.d.C., S.M., H.B., S.Z., X.Z., N.T.B., J.A.C., D.P.H., D.B., G.Z., G.K.M., L.P., and M.M. performed research; M.R.N., A.B., and C.S. contributed new reagents/analytic tools; B.L.L., D.M., J.F.D., N.Z., D.d.C., S.M., H.B., S.Z., X.Z., N.T.B., J.A.C., D.P.H., D.B., G.K.M., M.J.R., D.W., G.R., H.S.Q., S.M.W., J.J.K., A.S., M.M.M., D.A.K., and S.S.P. analyzed data; and B.L.L., G.R., A.S., D.A.K., and S.S.P. wrote the paper.
Conflict of interest statement: D.M., J.F.D., L.P., D.W., G.R., S.M.W., S.Z., H.S.Q, J.J.K, A.S., and S.S.P. are full-time employees of Boehringer Ingelheim Pharmaceuticals, Inc. M.M, M.R.N, A.B., and C.S. were full-time employees of Boehringer Ingelheim Pharmaceuticals, Inc. A.B. and M.R.N. are listed as coinventors on a US provisional patent application filed by Boehringer Ingelheim Pharmaceuticals, Inc. relevant to this work. J.F.D., N.Z., D.d.C., X.Z., N.T.B., J.A.C., D.P.H., and M.M.M. were employees of Hydra Biosciences, and received options. This work was supported in part by Boehringer Ingelheim Pharmaceuticals, Inc.
This article is a PNAS Direct Submission.
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