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Aims/hypothesis To study the effects of genetic deficiency of aldose reductase (AR) on the development of key end points of diabetic nephropathy.Methods A line of AR knockout (KO), a line ofAR bitransgenics (BT) and the control C57BL/6 mice were used in the study.The KO and BT mice were both deficient for AR in the renal glomeruli and all other tissues except that in the BT mice, a knockin-transgene directs collecting tubule epithelial cell-specific AR expression.Diabetes was induced in eight-week old male mice with streptozotocin.Mice were further maintained for 17 weeks then killed.A number of serum and urinary parameters were determined for these 25-week old mice.Periodic acid-Schiff staining, Western blots, immunohistochemistry and Protein kinase C (PKC) activity assays were performed for histological analyses, the expression of collagen Ⅳ and transforming growth factor β 1 (TGF-β 1) and PKC activities in renal cortical tissues respectively.Results Diabetes-induced extracellular matrix accumulation and collagen Ⅳ overexpression were completely prevented in diabetic (AR) KO and BT mice.AR deficiency also completely or partially prevented diabetes-induced activation of renal cortical PKC, TGF-β1 and glomerular hypertrophy.Loss of AR results in a 43% reduction in urine albumin excretion in the diabetic KO mice and a 48% reduction in the diabetic BT mice (p<0.01).Conclusions/interpretation Genetic deficiency of AR significantly ameliorated development of key endpoints linked with early diabetic nephropathy in vivo.Robust and specific inhibition of AR might be an effective strategy for the prevention and treatment of diabetic nephropathy.