Abstract P033: Acute Intravenous Glucose Injection Inhibits Tubuloglomerular Feedback and Increase Glomerular Filtration Rate
Hyperfiltration is considered a risk factor for diabetic nephropathy, but the mechanism for alterations in glomerular filtration rate (GFR) in diabetes has not been clarified. Nitric oxide synthase 1 (NOS1) highly expresses in the macula densa (MD) and NO inhibits tubuloglomerular feedback (TGF). TGF is one of the major mechanisms for glomerular filtration rate (GFR) regulation. It is not clear whether glucose itself filtered into the tubules has any effect on GFR. We hypothesized the glucose enhances NOS1 activity in the MD, which blunts TGF and increases GFR.
First, we measured GRF in conscious mice by plasma FITC-inulin clearance. Three min after an intravenous infusion of 50μl of 4M glucose in wild type mice, GFR was increased by 19.1% from 236±9.7 to 281±13.4 μl/min. Intravenous saline infusion had no effect on GFR.
NO generation by the MD was then measured in isolated perfused juxtaglomerular apparatus with fluorescent probe DAF-2DA. In response to an increase in tubular glucose concentration from 0 to 300 mg/dl, NO production was increased by 78.4%. TGF, assessed in vivo by measuring the change in proximal tubular stop flow pressure (Δ) induced by an increase of perfusion rate in late proximal tubules from 0 to 40 nl/min, was significantly blunted from 6.5±0.9 to 5.0±1.6 mmHg when tubular perfusate glucose concentration was increased 0 to 300 mg/dl.
To determine whether the glucose-induced changes were mediated by NOS1 in MD, we repeated the experiments in MD specific NOS1 KO (MD-NOS1KO) mice. Intravenous glucose infusion did not significantly increase GRF (from 203±15.7 to 220±6.9 μl/min) in the KO mice. Elevating glucose content in tubular perfusate did not alter the TGF response (Δ was from 7.8±1.3 to 7.3±2.1 mmHg) in MD-NOS1KO mice. We concluded that increase of tubular glucose concentration increases GFR by inhibiting TGF response, which is mediated by NO production from NOS1 in the MD.
Author Disclosures: J. Zhang: None. Y. Lu: None. J. Wei: None. K. Yip: None. R. Liu: None.
- © 2015 by American Heart Association, Inc.