Ginsenoside Rd attenuates renal aging and fibrosis through inhibition of angiotensin II type 1 receptor signaling.

<h4>Background</h4>Renal cellular senescence(definition)-characterized by the accumulation of extracellular matrix and the consequent development of fibrosis-is a major contributor to accelerated renal aging. Despite its clinical significance, effective antifibrotic therapies remain limited due to the complex pathophysiology of kidney fibrosis.<h4>Purpose</h4>This study aimed to identify a novel pharmacological agent that counteracts renal fibrosis and cellular senescence associated with aging and injury.<h4>Methods</h4>We evaluated the effects of ginsenoside Rd (GRd) in aged mice and multiple kidney injury models, including cisplatin-induced acute kidney injury and adenine-induced chronic kidney disease. Renal function, fibrosis, and senescence markers were assessed following GRd administration.<h4>Results</h4>GRd administration attenuated renal damage, reduced senescent cell burden, and suppressed fibrotic remodeling in aged mice and in multiple kidney injury models. Mechanistically, GRd disrupted angiotensin II (Ang II)-mediated signaling by acting as a competitive antagonist at the Ang II type 1 receptor (AT1R), thereby blocking downstream oxidative stress and DNA damage response pathways involving p16, p21, and p53. Consequently, GRd treatment resulted in a reduced accumulation of senescent cells and a decrease in the expression of senescence-associated secretory phenotype (SASP) factors in vivo. GRd-treated kidneys ultimately exhibited significantly reduced fibrosis and improved functional outcomes.<h4>Conclusion</h4>These findings highlight GRd as a promising therapeutic candidate for preventing or ameliorating renal aging and fibrosis in both acute and chronic kidney injury contexts.