Modulation of single-nephron GFR in the db/db mouse model of type 2 diabetes mellitus. II. Effects of renal mass reduction.
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.
Levine
David Z
DZ
The Kidney Research Centre, Ottawa Hospital Research Institute and University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada.
Iacovitti
Michelle
M
Robertson
Susan J
SJ
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005246:Feedback / Q000502:physiology; D005919:Glomerular Filtration Rate / Q000502:physiology*; D007668:Kidney / Q000473:pathology* / Q000503:physiopathology; D007687:Kidney Tubules, Proximal / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009392:Nephrectomy; D009399:Nephrons / Q000503:physiopathology*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors; D009929:Organ Size / Q000502:physiology
D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse