Therapeutic strategies for hypertension: exploring the role of microbiota-derived short-chain fatty acids in kidney physiology and development.

Gut microbiota have emerged as a key regulator of systemic health, influencing various physiological processes, including kidney development, function, and blood pressure regulation. This review highlights the role of microbiota-derived short-chain fatty acids (SCFAs), primarily acetate, propionate, and butyrate, in the gut-kidney axis, focusing on their signaling mechanisms, vascular effects, and developmental implications. Evidence suggests that SCFAs modulate kidney development and function and exert anti-inflammatory, antioxidant, and vasoregulatory effects through specific G protein-coupled receptors (GPR41, GPR43, GPR109A, OLFR78, and OLFR558). Human studies and research using genetically modified animals have demonstrated that gut dysbiosis disrupts SCFA metabolism, potentially contributing to hypertension, endothelial dysfunction, and chronic kidney disease (CKD). Germ-free microbiota-transplantation studies revealed that the presence of gut microbiota directly influences vascular tone and systemic blood pressure via SCFA-mediated mechanisms. Furthermore, acetate, a SCFA, is shown to impact fetal kidney development and nephron progenitor cell dynamics. Sex-specific effects of gut microbiota on vascular remodeling and immune responses further highlight the complexity of microbiome-host interactions. In pediatric patients, altered SCFA profiles are associated with CKD progression and relapse in nephrotic syndrome. Clinical data suggest that plasma SCFA levels may serve as biomarkers for hypertension risk and cardiovascular outcomes in children with kidney disease. Therapeutically, interventions targeting SCFA pathways, such as probiotics, prebiotics, dietary fiber diet, and receptor agonists, may help restore gut-kidney axis balance and improve kidney and cardiovascular outcomes. This review illustrates the critical role of SCFAs as mediators linking the gut microbiota to kidney and vascular health. Continued investigation into SCFA signaling may uncover novel strategies for preventing and managing hypertension, CKD, and developmental nephropathies.