Abstract
BACKGROUND: The current understanding of diabetic kidney disease (DKD) has significant gaps regarding the underlying pathogenesis. In this study, we aimed to characterize the temporal progression of DKD using a state-of-the-art mouse model of hypertension-accelerated disease, integrating kidney biomarker analysis, histopathology, and glomerular transcriptomic profiling. METHODS: Female diabetic db/db mice received a single intravenous dose of adeno-associated virus-mediated renin overexpression (ReninAAV, week 5) and underwent uninephrectomy (UNx, week 4). db/db UNx-ReninAAV mice were terminated at weeks 1, 4, 8, and 12 (n = 7-8 per group). Female db/m mice were used as healthy controls. Study endpoints included plasma and urine biochemistry, glomerulosclerosis scoring, quantitative kidney histology, and RNA sequencing of glomeruli isolated using laser-capture microdissection. RESULTS: db/db UNx-ReninAAV mice developed progressive albuminuria (from week 4) and glomerulosclerosis (from week 8). A pathway analysis of clustered gene regulations revealed broad glomerular transcriptome perturbations with signatures of increased extracellular matrix (ECM) turnover from week 8 and early onset of metabolic dysfunction. Markers of glomerular cell types and injury exhibited temporal regulation over the course of DKD, with early and sustained downregulation of endothelial markers, heterogeneous regulation of podocyte markers, and significant mesangial and parietal epithelial aberrations. Furthermore, the upregulation of cell injury markers confirmed progressive glomerular injury in the model. CONCLUSION: The db/db UNx-ReninAAV mouse model exhibits distinct temporal dynamics in glomerular cell markers, metabolic dysregulation, ECM remodeling, and injury. Together, these results highlight the utility of the db/db UNx-ReninAAV model as a relevant preclinical platform for studying progressive DKD.