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

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.

Scoping Review and Meta-analysis of Hyperbaric Oxygen Therapy for Radiation-Induced Hemorrhagic Cystitis.

PURPOSE OF REVIEW: To critically review and summarize existing literature assessing the effectiveness of hyperbaric oxygen therapy (HBOT) for the treatment of radiation-induced urologic injury. RECENT FINDINGS: Though 5 of the included 13 studies were published in the last 2-3 years, the only randomized controlled study was performed in 2012. Recent studies have confirmed the safety and efficacy of HBOT as well as identified risk factors for success vs. failure of HBOT for hemorrhagic radiation cystitis (HRC). Of the 602 patients that received HBOT for HRC, 84% had a partial or complete resolution. In the 7 studies that utilized RTOG/EORTC, 75% of patients saw an improvement in hematuria of at least one grade (out of possible 5 total). Of the 499 patients with documented follow-up, 14% experienced recurrence, with a median time to recurrence of 10 months (6 to 16.5 months).