THE ROLE OF GUT METABOLITE-SENSING RECEPTORS GPR41 AND GPR43 IN CARDIOVASCULAR DISEASE

Abstract

Objective: Fibre intake is associated with lower incidence of hypertension and cardiovascular mortality. Prebiotic fibre, such as resistant starches and soluble fibre, are fermented by commensal gut microbiota to short-chain fatty acids (SCFAs), which have a protective role in cardiovascular disease. We, and now others, have shown that supplementation of SCFA such as acetate, propionate and butyrate can reduce blood pressure (BP) and their complications. The main receptors for SCFAs, the G-coupled protein receptors GPR41 and GPR43, have redundant functions, but their contribution to cardiovascular health and disease is uncertain. Therefore, we aimed to characterize their contribution to the cardiovascular phenotype using a unique mouse model where both receptors are absent, the GPR41/43 knockout (KO) Design and method: We studied female (n = 12) and male (n = 15) double GPPR41/43 KO mice compared to wild-type (WT) C57BL/6 mice (n = 4–8) at 10 weeks of age. We performed BP measurements using tail cuff, sodium and water loading, real-time PCR, flow-cytometry of immune cells, and histology of the heart, kidney and gut Results: GPR41/43 KO male and female mice did not have significant difference in BP compared to WT mice (P = 0.387–0.676), but female GPR41/43 KO had significantly smaller kidneys (adjusted to tibia length) compared to WT female (P = 0.006). Upon saline challenge, both male and female GPR41/43 KO mice excreted more urine (P = 0.01 male, P = 0.116 female), but not sodium (P = 0.461 male, P = 0.141 female), compared to WT mice over a 5 hour period. GPR41/43 KO had lower levels of pro-renin receptor (Atp6ap2) mRNA (P = 0.012 male, P = 0.057 female) but higher levels of renal collagen genes mRNA (Col3a1 P = 0.055 male, Col1a1 P = 0.023 female), indicative of fibrosis. Conclusions: GPR41/43 KO mice expressed lower pro-renin receptor mRNA but higher levels of fibrosis markers. GPR41/43 KO mice excreted more urine than WT mice and did not have higher BP. Moreover, female GPR41/43 KO mice had significantly smaller kidneys, proposing a role for these receptors in renal development. Together, these findings suggest that the gut metabolite-sensing receptors GPR41/43 are likely to contribute to cardiovascular regulation via a role in water absorption and excretion, as well as in fibrosis