Linking epigenetic regulation of short chain fatty acid receptors, gut microbiome and hydrogen sulfide in the hypertensive kidney

Abstract

Hypertension is one of the leading causes of chronic kidney disease. Recent studies have highlighted the importance of gut microbiota on physiological processes, such as metabolism and immunity, through production of short chain fatty acids (SCFA), which are linked with blood pressure (BP) regulation. Moreover, host epigenetic regulators, such as microRNAs, can directly affect the microbiome, and therefore blood pressure. However, the precise epigenetic regulation of BP is poorly understood. The gaseous molecule, hydrogen sulfide (H2S) is involved in regulating several physiological processes, however, its role and influence on the host gut microbiome and on renal function remains to be elucidated. In this study, we sought to determine the roles of host microRNAs in regulating short chain fatty acid receptors in the hypertensive kidney and whether H2S donor, GYY4137 (GYY), could reverse the effects to mitigate renal dysfunction. C57BL6/J wild‐type mice were treated without or with Ang‐II (1000ng/kg−1/min−1) and GYY (133μM/kg−1/d−1) for 4 weeks. Quantitative PCR, Western blot, immunofluorescence assays, metagenomic sequencing, and glomerular filtration rate were measured. Results indicated that increased expression of miR‐329 and miR‐132 in hypertensive mice were reduced by GYY treatment. SCFA receptors Gpr41 and Gpr43 are expressed in the kidney and are also predicted targets of miR‐329 and miR‐132, respectively. The mRNA and protein expression of the above receptors was reduced in Ang‐II treated mice while animals treated with Ang‐II and GYY showed normalized expression. miR‐129 was induced by GYY supplementation and the predicted SCFA receptor target Olfr78 was decreased in the normal kidney with the opposite effect in hypertensive kidney. Immunofluorescence analysis showed decreased signal of Gpr41 and Gpr43 in the blood vessel and tubules in Ang‐II mice and were normalized in mice treated with GYY. Metagenomic sequencing showed H2S supplementation affected the host gut microbiome composition and improved renal function. In conclusion, our data suggests that microRNAs can regulate SCFA receptors in the kidney and hydrogen sulfide supplementation has a positive effect on renal function through the gut microbiome and SCFA receptors.Support or Funding InformationDK‐104653 and HL‐104103 to U.S.,15SDG25840013 to S.P.