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; IC 50 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 10156-10161 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 116 |
| Issue number | 20 |
| DOIs | |
| State | Published - May 14 2019 |
Fingerprint
Keywords
- Calcium
- Fibrosis
- Ion channels
- Nuclear factor of activated T cells
- TRPC6
ASJC Scopus subject areas
- General
Cite this
In vivo selective inhibition of TRPC6 by antagonist BI 749327 ameliorates fibrosis and dysfunction in cardiac and renal disease. / Lin, Brian Leei; Matera, Damian; Doerner, Julia F.; Zheng, Nan; Del Camino, Donato; Mishra, Sumita; Bian, Hong; Zeveleva, Svetlana; Zhen, Xiaoguang; Blair, Nathaniel T.; Chong, Jayhong A.; Hessler, David P.; Bedja, Djahida; Zhu, Guangshuo; Muller, Grace K.; Ranek, Mark; Pantages, Lynn; McFarland, Mary; Netherton, Matthew R.; Berry, Angela; Wong, Diane; Rast, Georg; Qian, Hu Sheng; Weldon, Steven M.; Kuo, Jay J.; Sauer, Achim; Sarko, Chris; Moran, Magdalene M.; Kass, David A; Pullen, Steven S.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 20, 14.05.2019, p. 10156-10161.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - In vivo selective inhibition of TRPC6 by antagonist BI 749327 ameliorates fibrosis and dysfunction in cardiac and renal disease
AU - Lin, Brian Leei
AU - Matera, Damian
AU - Doerner, Julia F.
AU - Zheng, Nan
AU - Del Camino, Donato
AU - Mishra, Sumita
AU - Bian, Hong
AU - Zeveleva, Svetlana
AU - Zhen, Xiaoguang
AU - Blair, Nathaniel T.
AU - Chong, Jayhong A.
AU - Hessler, David P.
AU - Bedja, Djahida
AU - Zhu, Guangshuo
AU - Muller, Grace K.
AU - Ranek, Mark
AU - Pantages, Lynn
AU - McFarland, Mary
AU - Netherton, Matthew R.
AU - Berry, Angela
AU - Wong, Diane
AU - Rast, Georg
AU - Qian, Hu Sheng
AU - Weldon, Steven M.
AU - Kuo, Jay J.
AU - Sauer, Achim
AU - Sarko, Chris
AU - Moran, Magdalene M.
AU - Kass, David A
AU - Pullen, Steven S.
PY - 2019/5/14
Y1 - 2019/5/14
N2 - 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; IC 50 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.
AB - 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; IC 50 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.
KW - Calcium
KW - Fibrosis
KW - Ion channels
KW - Nuclear factor of activated T cells
KW - TRPC6
UR - http://www.scopus.com/inward/record.url?scp=85065721210&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85065721210&partnerID=8YFLogxK
U2 - 10.1073/pnas.1815354116
DO - 10.1073/pnas.1815354116
M3 - Article
C2 - 31028142
AN - SCOPUS:85065721210
VL - 116
SP - 10156
EP - 10161
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 20
ER -