Targeting microRNA-132 protects against kidney fibrosis and restricts myofibroblast differentiation from cells of renin lineage.

Abstract

Kidney fibrosis represents a central pathophysiological process in the progression of chronic kidney disease to end-stage kidney failure, yet its underlying cellular mechanisms remain incompletely understood. Cells of renin lineage (CoRL) have been shown to possess regenerative capacity following injury, but may also contribute to fibrotic remodeling. MicroRNA-132 (miR-132), known to regulate both fibrotic signaling and renin synthesis, represents a potential therapeutic target to halt progression of kidney fibrosis. Here, we investigated the role of miR-132 and CoRL in two complementary models of kidney injury-5/6 nephrectomy (5/6NX) and bilateral ischemia-reperfusion injury (bIRI)-using renin lineage-tracing mice treated with a miR-132 antimiR or scrambled control. In both models, miR-132 silencing improved renal function and led to a consistent reduction in interstitial fibrosis and myofibroblast accumulation in the kidney. The number of proliferating myofibroblasts also declined, supporting an antiproliferative effect. Podocyte number per glomerulus was significantly higher upon miR-132 silencing, indicating protection from glomerular damage. CoRL-derived podocytes were present in both models, but not affected by miR-132 knockdown, suggesting that the observed podocyte protection primarily results from reduced loss of resident cells. Lineage tracing further confirmed that CoRL contribute directly to the pool of αSMA+ myofibroblasts. Interestingly, miR-132 silencing reduced the number of CoRL-derived myofibroblasts. Together, these findings identify miR-132 as a regulator of fibrotic remodeling and highlight the dual regenerative and fibrogenic potential of CoRL. Pharmacological inhibition of miR-132 may offer a promising approach to preserve kidney function and limiting fibrosis.