Tubular atrophy, interstitial fibrosis, and inflammation in type 2 diabetic db/db mice. An accelerated model of advanced diabetic nephropathy

Objective: Advanced diabetic nephropathy (DN) is difficult to address experimentally in mice because available models of DN lack global glomerulosclerosis and major tubulointerstitial pathology. Accelerating the development of DN in mice would be desirable for feasible experimental validation of potential targets that mediate the progression to late stage DN. Methods: 6 week old male db/db mice underwent uninephrectomy and the development of nephropathy was compared to wild-type mice and sham-operated db/db mice. Results: Uninephrectomy at young age was associated with increased albuminuria and severe glomerulosclerosis in 37% of glomeruli at 24 weeks of age as compared to sham-operated db/db mice (8%). Uninephrectomy also increased the number of glomerular macrophages in db/db mice. The uninephrectomy-related acceleration of glomerular damage was associated with significant tubulointerstitial injury as indicated by an increase in indices of tubular cell damage, tubular dilatation, and expansion of interstitial volume. Uninephrectomy markedly increased the renal mRNA expression of Mcp-1/Ccl2, Tgf-beta, and collagen I. Conclusion: Early uninephrectomy can accelerate the development of advanced DN in db/db mice which may be instrumental in the design of interventional studies that intend to focus on the molecular pathology of the progression to late stage DN.