Thick Ascending Limb‐Specific NOS1 Knockout Reduces Urinary Osmolality in Type 1 Diabetes

Abstract

Diabetic (T1D) animal models show upregulated nitric oxide (NO) production and NO synthase 1 (NOS1) activity in renal medullary thick ascending limb (TAL). Because NO reduces Na+ transport by the TAL, we hypothesized that TAL‐specific NOS1 knockout (KO) mice develop fluid‐electrolyte dysfunction with T1D. NOS1flox (n=10–12) and TAL NOS1 KO mice (n=6–9) were administered streptozotocin (STZ; 150 mg/kg, ip), and systolic blood pressure (SBP), electrolytes, and urine osmolality monitored. After 7 wks of T1D, NOS1flox and TAL NOS1 KO mice did not differ with regard to SBP (119±4 vs 120±3 mmHg), blood glucose (460±58 vs 511±42 mg/dl), body weight (25.0±1.6 vs 24.5±0.9 g), water consumption (8.3±3.5 vs 14.6±4.2 ml/day) or protein excretion (3.5±1.4 vs 4.12±0.8 mg protein/day). Post‐T1D urine flow was greater in TAL NOS1 KO than NOS1flox mice (9.5±3.3 vs 5.0±2.3 ml/day; p=0.04). T1D led to reduced urinary osmolality in TAL NOS1 KO mice (Baseline=2832±448 mOsm/kg; T1D=1287±195 mOsm/kg; p<0.05), an effect significantly different from NOS1flox mice (Baseline=2625±270 mOsm/kg; T1D=2117± 228 mOsm/kg; p(genotype x T1D)<0.05). T1D did not alter Na+ or K+ excretion in either group. In conclusion, the loss of NOS1 in the TAL altered TID‐induced urine output and osmolality suggesting that TAL NOS1‐derived NO is critical to maintain fluid‐electrolyte homeostasis during T1D.