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

Renal cellular senescence-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.

This study aimed to identify a novel pharmacological agent that counteracts renal fibrosis and cellular senescence associated with aging and injury.

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.

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.

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.