This study examines for the first time the effects of uninephrectomy (Nx) on modulation of whole kidney GFR, single nephron GFR (SNGFR) and progression of diabetic nephropathy in the db/db mouse model of type 2 diabetes mellitus. To characterize SNGFR and tubuloglomerular feedback (TGF) responses to Nx and chronic neuronal nitric oxide synthase (nNOS) inhibition in the db/db mouse, we studied the effects of Nx on whole kidney GFR, SNGFR and TGF characteristics in both db/db and WT mice after Nx or sham Nx. We also documented progression of glomerular changes over a six month period. Whole kidney GFR and SNGFR in db/db Nx mice were significantly higher than in db/db sham mice, without change in proximal tubule reabsorptive rates. The TGF responses, determined as proximal-distal SNGFR differences, were brisk (WT sham, 12.1 ±1.0 vs. 8.4 ±.6 nl/min, p<0.05; WT Nx 15.7±1 vs. 12.0 ± 1 nl/min, p<0.05; db/db Nx, 17.8 ±1.3 vs. 14.3 ± 1 nl/min, p<0.05). Chronic ingestion of the nNOS inhibitor, S-methylthiocitrulline, for 2-3 weeks post Nx had no effect on SNGFR or the TGF response. These studies show that after Nx, these hyperglycemic morbidly obese db/db mice have further elevations in whole kidney and single nephron GFR with an intact TGF system. In addition, in the db/db Nx mice, 4-6 months post Nx, there is an exacerbation of the lesions of diabetic nephropathy as quantified by a significant increase in the ratio of mesangial surface area to total glomerular surface area.