Sex-dependent differences in the progression of renal injury and fibrosis following ischemic acute kidney injury.

Abstract

Sex differences critically influence the renal response to ischemic injury, yet the mechanisms underlying differing recovery between males and females remain incompletely understood. Using a unilateral ischemia-reperfusion model with contralateral nephrectomy (uIRIx), we performed a longitudinal analysis of the transition from acute kidney injury (AKI) to chronic kidney disease (CKD) in male and female mice following uIRIx over 98 days. Male mice developed sustained renal dysfunction, characterized by persistent proteinuria, a marked reduction in glomerular filtration rate, and progressive increases in urinary albumin/creatinine ratio, consistent with an ongoing functional decline. Histologically, males displayed extensive tubular dilation, interstitial fibrosis, and elevated kidney injury molecule-1 expression, together with persistent macrophage and T-cell infiltration indicative of unresolved inflammation. In contrast, females exhibited partial functional recovery with improved glomerular filtration rate, reduced proteinuria, and attenuated structural damage, including less fibrosis and tubular injury across all timepoints. Morphometric analysis revealed smaller glomerular cross-sectional areas in males at day 14, suggesting early maladaptive remodelling, whereas females demonstrated adaptive hypertrophy that may preserve filtration capacity. Assessment of peritubular capillaries (CD31) indicated more effective microvascular preservation in females, consistent with estrogen-mediated endothelial protection. Collectively, these findings demonstrate that females are protected from the maladaptive progression of ischemic AKI to CKD, highlighting longitudinal sex-specific dynamics in renal repair and chronic disease development.