Generating a model of accelerated murine diabetic nephropathy

This journal suppl. entitled: Special Issue: 11th Asian Pacific Congress of Nephrology, incorporating the 15th Asian Colloquium in Nephrology and 2nd Asian Forum of CKD Initiative, Kuala Lumpur, MalaysiaINTRODUCTION: One major limitation of mouse models of diabetic nephropathy (DN) is the absence of significant renal failure. Although genetically diabetic db/db mice displays moderate glomerular pathology, decline in GFR is usually modest even after prolonged periods of observation, making it difficult to investigate the therapeutic impact of potentially renoprotective drugs in DN. MATERIALS AND METHODS: db/db mice (n = 24) underwent partial renal ablation by uninephrectomy or sham operation at 10 weeks of age to hasten the development of typical glomerular abnormalities, and nondiabetic db/m mice (n = 24) were subjected to the same treatments. Mice were sacrificed at 18 weeks. RESULTS: Compared with their nondiabetic db/m littermates, db/db mice had significantly higher body weight, blood glucose (BG), and urine albumin-tocreatinine ratio (ACR) at baseline, but serum creatinine (sCr) was not different. Uninephrectomized db/db mice had higher sCr (0.95 1 0.05 vs 0.64 1 0.04 mg/dL, P < 0.001), ACR (1997 1 96 vs 1579 1 50 mg/mg, P < 0.001), and more severe glomerular (P < 0.001) and interstitial (P = 0.001) lesions than sham-operated db/db mice. There was significant upregulation of renal cortical mRNA and protein expression of CCL2, ICAM-1, and MIP-2 (the murine equivalent of human CXCL8) in db/db vs db/m mice, which was further enhanced by uninephrectomy. Uninephrectomy per se did not affect glomerular nephrin expression in db/db or db/m mice. CONCLUSION: Uninephrectomy markedly accelerates and exaggerates renal lesions and inflammation in diabetic db/db mice