Targeting liver angiotensinogen with siRNA enhances podocyte regeneration through renin lineage cells in experimental kidney disease.

Targeting angiotensinogen (AGT) with small interfering RNAs (siRNAs) is a promising strategy to suppress renin-angiotensin system (RAS) activity and to potentially mitigate progression of chronic kidney disease (CKD). Although AGT siRNAs have been shown to exert kidney-protective effects in experimental models of kidney injury, the underlying mechanisms remain unclear. Juxtaglomerular cells of renin lineage (CoRL) have recently been recognized as progenitors capable of replenishing several glomerular cell types during injury. Here, we investigated whether AGT siRNA alters CoRL-driven glomerular cell repopulation in the 5/6 nephrectomy (5/6NX) model using renin lineage-tracing mice treated with either AGT siRNA or luciferase-targeting control. AGT silencing achieved ∼85% reduction in plasma AGT and induced a marked compensatory rise in plasma renin concentration. Despite these systemic effects, AGT knockdown did not alter kidney function, as reflected by unaffected blood urea levels, urinary albumin-to-creatinine ratios, glomerular hypertrophy, or kidney fibrosis. While the number of CoRL-derived mesangial cells remained unchanged, AGT inhibition resulted in a modest but significant increase in CoRL-derived parietal epithelial cells and a pronounced increase in CoRL-derived podocytes. These findings indicate that liver-directed AGT silencing does not confer short-term functional benefit but enhances CoRL-mediated podocyte regeneration, identifying a potential mechanism that may contribute to delayed renal repair.