Impaired urinary nitrates plus nitrites (UNOx) in high‐NaCl fed Ksp‐cadherin‐targeted insulin receptor knockout (KO) mice is insensitive to Tempol

Abstract

Previously, we showed significantly reduced UNOx in mice lacking the insulin receptor in renal tubule (primarily distal) by targeted knockout. To address the possibility that increased destruction of NO by superoxide in the KO might explain these findings, 3-month-old male KO and WT littermates were fed serially medium- (0.5% NaCl, MS), low- (0.08% NaCl, LS), and high-NaCl (5% NaCl, HS) diets for one week each followed by a week of HS plus 3 mM Tempol, a superoxide dismutase mimetic, in drinking water. On day 5 each week, 24-hr urine was collected. Starting body weights (BW) were not different. However, final BWs were significantly higher in KO mice (g): 30.5 ± 0.7, WT versus 33.1 ± 0.4, KO, p = 0.03. Urine volumes, sodium or potassium were not significantly different between genotypes under any condition. No genotypic differences in UNOx were observed when mice were fed the LS diet (μmol/kg·bw/d): 28.6 ± 4.0, WT and 27.4 ± 5.7, KO, p = 0.87. HS feeding led to a small decrease in WT, but decreased UNOx in KO by over 50% (20.2 ± 4.3, WT and 11.3 ± 0.5, KO, p = 0.057). Tempol did not correct this difference, nor significantly affect WT levels of UNOx (21.1 ± 2.3, WT and 9.2 ± 2.7, KO, p = 0.036). Our results suggest that KO mice are more sensitive to HS feeding with regard to UNOX and weight gain. This deficit in UNOx does not appear to be due to relatively increased superoxide activity. Thus genotypic differences may be the result of reduced NO production.