Sex-dependent and compartment-specific macrophage accumulation associates with glomerular injury in BTBR ob/ob mice.

Abstract

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by chronic hyperglycemia and represents a growing global health burden. One of its major complications is diabetic kidney disease (DKD), a progressive condition characterized by declining kidney function accompanied by structural alterations in tissue. Among the multiple pathways involved in DKD progression, inflammation has emerged as a key contributor. In parallel, increasing evidence suggests that biological sex influences disease progression; however, whether and how sex modulates inflammatory mechanisms driving DKD progression remains incompletely understood. In this study, we investigated the interplay between inflammation and biological sex in DKD using the BTBR ob/ob model, which closely recapitulates the human disease. Obese diabetic mice exhibited significant albuminuria regardless of sex; however, podocyte-associated proteins displayed sex-dependent molecular regulation. At the inflammatory level, no changes were detected in whole-kidney analyses based on the selected markers, but a compartment-specific response was observed, characterized by increased macrophage infiltration and upregulation of Ccl2 (MCP-1) gene expression in the glomerular compartment, especially in males. Additionally, the tubular compartment exhibited distinct sex- and metabolism-dependent inflammatory gene expression patterns. Together, these findings indicate that inflammation in this model is spatially compartmentalized and also differentially regulated according to sex. This integrated perspective may contribute to a better understanding of DKD progression and support the development of more precise and targeted therapeutic strategies.