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RENAL HEMODYNAMICS AND CARDIORENAL INTEGRATION

Modulation of single-nephron GFR in the db/db mouse model of type 2 diabetes mellitus. II. Effects of renal mass reduction

¹Division of Nephrology, The Kidney Research Centre, Ottawa Health Research Institute, and ²Department of Pathology, University of Ottawa, Ottawa, Ontario, Canada

Submitted 26 June 2007 ; accepted in final form 10 April 2008

This study examines for the first time the effects of uninephrectomy (Nx) on modulation of whole kidney glomerular filtration rate (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 inhibition in the db/db mouse, we studied the effects of Nx on whole kidney GFR, SNGFR, and TGF characteristics in db/db and wild-type (WT) mice after Nx or sham Nx. We also documented progression of glomerular changes over a 6-mo period. Whole kidney GFR and SNGFR were significantly higher in db/db Nx than db/db sham mice, without change in proximal tubule reabsorptive rates. The TGF responses, determined as proximal-distal SNGFR differences, were brisk: 12.1 ± 1.0 vs. 8.4 ± 0.6 nl/min in WT sham (P < 0.05), 15.7 ± 1.0 vs. 12.0 ± 1.0 nl/min in WT Nx (P < 0.05), and 17.8 ± 1.3 vs. 14.3 ± 1.0 nl/min in db/db Nx (P < 0.05) mice. Chronic ingestion of the neuronal nitric oxide synthase inhibitor S-methylthiocitrulline for 2–3 wk after Nx had no effect on SNGFR or the TGF response. These studies show further elevations in whole kidney GFR and SNGFR in these hyperglycemic morbidly obese db/db mice, with an intact TGF system after Nx. In addition, in the db/db Nx mice, 4–6 mo after Nx, there was 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.

hyperfiltration; tubuloglomerular feedback; neuronal nitric oxide synthase