Receptor GPR91 contributes to voiding function and detrusor relaxation mediated by succinate

Abstract

Aim: Succinate activates the receptor GPR91 identified in the bladder. The present study aims to unravel the mechanisms of bladder relaxation by succinate and how the receptor is involved in structural and functional changes of the bladder. Methods: Physiological recordings of bladder function were carried out by cystometry and organ bath from C57BL/6 mice, homozygous GPR91 −/− mice, and Sprague-Dawley (SD) rats. GPR91 expression was confirmed by polymerase chain reaction and tissue morphology was examined by light (Masson trichrome) and fluorescence microscopy. Nitric oxide (NO) and ATP secretion were measured. Results: Bladders of GPR91 KO mice had a greater mass to body weight ratio with a thicker bladder wall compared to C57BL/6 mice. They also displayed increased basal and maximal bladder pressures, and decreased intercontraction intervals, bladder capacity, micturition volume, and compliance. During cystometry, bladders of SD rats and C57BL/6 mice instilled with succinate (10 mM) showed signs of relaxation while bladders of GPR91 KO mice were unresponsive. Similarly, in organ bath, succinate relaxed bladder strips preincubated with carbachol, except GPR91 KO ones. Relaxation was stronger in the presence of urothelium and independent of NO synthesis. Bladder strips from all mice groups showed similar responses to KCl, carbachol, and electrical stimulation. In vitro, succinate increased NO secretion in urothelial cell culture of both C57BL6 and GPR91 KO mice while ATP secretion was potently decreased by succinate in C57BL6 culture only. Conclusion: Succinate through GPR91 is essential to bladder structure and contraction. GPR91 relaxes the detrusor partially by decreasing urothelial ATP secretion.

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“…Elevated succinate levels within the gut lumen association with microbiome disturbances (dysbiosis) and in patients with inflammatory bowel disease (IBD) and animal models of intestinal inflammation 120 . Physiologically, succinate activates the receptor GPR91 identified in the bladder and it is essential to bladder structure and contraction 129 .…”

Succinate as a New Actor in Pluripotency and Early Development?

“…Vascular endothelial cells of the juxtaglomerular apparatus express SUCNR1 and react to succinate exposure by increased [Ca 2+ ] i , production of nitric oxide and release of prostaglandin E2 (PGE2) [ 92 ]. However, the contribution of GPR91 to NO release might be questioned or might be cell type-specific as succinate increases NO secretion in the urothelial cell culture of both C57BL6 and GPR91 KO mice [ 93 ].…”