Increased systolic blood pressure and defective pressure‐natriuresis in mice lacking the insulin receptor in the thick ascending limb through collecting duct

Abstract

Insulin affects sodium excretion and blood pressure. In order to examine the role of the insulin receptor (IR) in the kidney, we selectively knocked out the IR from the thick ascending limb (TAL) through collecting duct (CD) of the renal tubule by using a cre-recombinase/lox P cross-breeding strategy with Cre driven by Ksp-cadherin in mice. Immunoblotting revealed band density for the β-subunit of IR was reduced to 22% of the WT mean in the inner stripe of the outer medulla (OMH) of the KO mice. Baseline systolic blood pressures, measured by radiotelemetry, were significantly increased in the KO mice in the light period (mm Hg): 123 ± 3 (KO) versus 109 ± 5 (WT), but not different in the dark period. Moreover, OMH endothelial nitric oxide synthase protein abundance was significantly decreased in KO mice to 63% of the WT level. To examine pressure natriuresis, we administered, by gavage, 25 ml/kg/bw of 15% dextrose in 0.9% saline. Dextrose was included to raise endogenous insulin levels. Urine was collected every two hours after gavage. Blood pressure was monitored. The mean arterial blood pressure (MAP) was significantly increased, relative to baseline, in both KO and WT mice at 30 minutes. After 30 minutes, MAP came back to baseline in WT mice, however in KO mice it remained elevated significantly until 120 minutes. Furthermore, the urinary sodium excretion between 2 and 4 hours after gavage was significantly increased in WT, but not in KO mice. When dextrose was not included there were no differences between genotypes in blood pressure or sodium excretion. These data suggest a role for the IR in the renal TAL through CD in facilitating pressure natriuresis which may involve endothelial nitric oxide synthase.