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In vivo selective inhibition of TRPC6 by antagonist BI 749327 ameliorates fibrosis and dysfunction in cardiac and renal disease.

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.

SUBMITTER: Lin BL

PROVIDER: S-EPMC6525474 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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In vivo selective inhibition of TRPC6 by antagonist BI 749327 ameliorates fibrosis and dysfunction in cardiac and renal disease.

Lin Brian Leei BL Matera Damian D Doerner Julia F JF Zheng Nan N Del Camino Donato D Mishra Sumita S Bian Hong H Zeveleva Svetlana S Zhen Xiaoguang X Blair Nathaniel T NT Chong Jayhong A JA Hessler David P DP Bedja Djahida D Zhu Guangshuo G Muller Grace K GK Ranek Mark J MJ Pantages Lynn L McFarland Mary M Netherton Matthew R MR Berry Angela A Wong Diane D Rast Georg G Qian Hu Sheng HS Weldon Steven M SM Kuo Jay J JJ Sauer Achim A Sarko Chris C Moran Magdalene M MM Kass David A DA Pullen Steven S SS

Proceedings of the National Academy of Sciences of the United States of America 20190426 20

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 a ...[more]

PMID: 31028142

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Project description:Diabetic nephropathy is characterized by excessive accumulation of extracellular matrix (ECM) leading to renal fibrosis, progressive deterioration of renal function, and eventually to end stage renal disease. Matrix metalloproteinases (MMPs) are known to regulate synthesis and degradation of the ECM. Earlier, we demonstrated that imbalanced MMPs promote adverse ECM remodeling leading to renal fibrosis in type-1 diabetes. Moreover, elevated macrophage infiltration, pro-inflammatory cytokines and epithelial‒mesenchymal transition (EMT) are known to contribute to the renal fibrosis. Various bioactive compounds derived from the medicinal plant, Azadirachta indica (neem) are shown to regulate inflammation and ECM proteins in different diseases. Nimbidiol is a neem-derived diterpenoid that is considered as a potential anti-diabetic compound due to its glucosidase inhibitory properties. We investigated whether Nimbidiol mitigates adverse ECM accumulation and renal fibrosis to improve kidney function in type-1 diabetes and the underlying mechanism. Wild-type (C57BL/6J) and type-1 diabetic (C57BL/6-Ins2Akita/J) mice were treated either with saline or with Nimbidiol (0.40 mg kg-1 d-1) for eight weeks. Diabetic kidney showed increased accumulation of M1 macrophages, elevated pro-inflammatory cytokines and EMT. In addition, upregulated MMP-9 and MMP-13, excessive collagen deposition in the glomerular and tubulointerstitial regions, and degradation of vascular elastin resulted to renal fibrosis in the Akita mice. These pathological changes in the diabetic mice were associated with functional impairments that include elevated resistive index and reduced blood flow in the renal cortex, and decreased glomerular filtration rate. Furthermore, TGF-β1, p-Smad2/3, p-P38, p-ERK1/2 and p-JNK were upregulated in diabetic kidney compared to WT mice. Treatment with Nimbidiol reversed the changes to alleviate inflammation, ECM accumulation and fibrosis and thus, improved renal function in Akita mice. Together, our results suggest that Nimbidiol attenuates inflammation and ECM accumulation and thereby, protects kidney from fibrosis and dysfunction possibly by inhibiting TGF-β/Smad and MAPK signaling pathways in type-1 diabetes.

Dataset Information

In vivo selective inhibition of TRPC6 by antagonist BI 749327 ameliorates fibrosis and dysfunction in cardiac and renal disease.

Publications

In vivo selective inhibition of TRPC6 by antagonist BI 749327 ameliorates fibrosis and dysfunction in cardiac and renal disease.

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