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1 Division of Nephrology, Kidney Research Centre, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada
2 Department of Pathology, University of Ottawa, Ottawa, Ontario, Canada
* To whom correspondence should be addressed. E-mail: dzlevine{at}rogers.com;dzlevine@uottawa.ca.
Hyperfiltration has been implicated in the progression to diabetic nephropathy in type 2 diabetes mellitus (DM2). This study focuses for the first time on the in vivo modulation of single nephron GFR (SNGFR) in the classic db/db (B6.Cg-m+/+Leprdb/J) mouse model of DM2. To obtain stable preparations, it was necessary to use a sustaining infusion of 3.3 ml/100 gm BWt.hr-1, or higher. SNGFR (measured both proximally and distally) was greater in db/db versus heterozygote (db/m) mice (p< 0.05) but not vs. the wild type (WT) mice. The tubuloglomerular feedback responses (TGF), determined as free-flow proximal vs distal SNGFR differences, were significant in db/db mice (11.6 ± 0.8 vs 9.3 ± 1.0 nl/min, p<0.01), in db/m mice (8.0 ± 0.8 vs 7.2 ± 0.6 nl/min, p< 0.02), and wild type (WT) mice (9.9 ± 0.6 vs 8.9± 0.7 nl/min, p< 0.05). After increasing the sustaining infusion in the db/db mice, to offset glycosuric urine losses, the SNGFR increased significantly, and the TGF response was abolished. In these volume replete db/db mice, absolute fluid reabsorption measured both at the late proximal and distal tubular sites were significantly increased versus db/m mice infused at 3.3 ml/100 gm BWt.hr-1. After infusion of the nNOS inhibitor SMTC, SNGFR fell in both db/db and db/m mice. These studies show that SNGFR is elevated in this mouse model of DM2, is suppressed by nNOS inhibition, and is modulated by TGF influences which are altered by the diabetic state and responsive to changes in ECF volume.
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