A novel glomerulopathy model demonstrates renal counterbalance via local angiotensin II regulation

Renal counterbalance, involving compensatory hypertrophy of the healthy kidney and atrophy of the injured one, remains incompletely understood, particularly at the glomerular level. In this study, we employed NEP25 mice, which selectively express human CD25 in podocytes, enabling precise induction of unilateral podocyte injury through the administration of LMB2, a CD25-targeted immunotoxin. Using a two-kidney, one-nephropathy (2K1N) model, we demonstrated that asymmetric changes in renal blood flow and proteinuria, with histological and transcriptomic analyses uncovering distinct pathological and molecular features between the injured and contralateral healthy kidneys. Notably, an imbalance in intrarenal angiotensin (Ang) II levels was observed, and angiotensin-converting enzyme inhibition ameliorated the glomerular damage and restored perfusion. These findings indicate that local Ang II dysregulation is a key factor in renal counterbalance. Our study provides the first glomerulopathy-based experimental platform to dissect asymmetric renal adaptation, offering fundamental insight into the homeostatic mechanisms of renal function in health and disease.