Salt sensitivity of nitric oxide generation and blood pressure in mice with targeted knockout of the insulin receptor from the renal tubule

Abstract

To elucidate the role of the insulin receptor (IR) on kidney nitric oxide generation and blood pressure (BP) control, we generated mice with targeted deletion of renal tubule IR using loxP recombination driven by a Ksp-cadherin promoter. Male knockout (KO) and wild-type (WT) littermates (~4 mo old) were transitioned through three 1-wk treatments: 1) low-NaCl diet (0.085%); 2) high-NaCl diet (HS; 5%); and 3) HS diet plus 3 mM tempol, a superoxide dismutase mimetic, in the drinking water. Mice were then switched to medium-NaCl (0.5%) diet for 5 days and kidneys harvested under pentobarbital anesthesia. Twenty-four-hour urinary nitrates plus nitrites were significantly higher in the WT mice under HS (2,067 ± 280 vs. 1,550 ± 230 nmol/day in WT and KO, respectively, P < 0.05). Tempol attenuated genotype differences in urinary nitrates plus nitrites. A rise in BP with HS was observed only in KO mice and not affected by tempol (mean arterial pressure, dark period, HS, 106 ± 5 vs. 119 ± 4 mmHg, for WT and KO, respectively, P < 0.05). Renal outer medullary protein levels of nitric oxide synthase (NOS) isoforms by Western blot (NOS1-3 and phosphorylated-S1177-NOS3) revealed significantly lower band density for NOS1 (130-kDa isoform) in the KO mice. A second study, when mice were euthanized under HS conditions, confirmed significantly lower NOS1 (130 kDa) in the KO, with an even more substantial (>50%) reduction of the 160-kDa NOS1 isoform. These studies suggest that the loss of renal IR signaling impairs renal nitric oxide production. This may be important in BP control, especially in insulin-resistant states, such as the metabolic syndrome.

Regulation of ENaC in mice lacking renal insulin receptors in the collecting duct

“…25). Recently, we also showed that this BP elevation was salt sensitive in those mice and possibly due to reduced renal nitric oxide synthase (NOS) activity (50). We believe this phenotype, however, may be a manifestation of reduced InsR in another cell type, perhaps the TAL, as blood pressure was actually slightly but significantly lower in the current model, i.e.…”

Differential circadian pattern of water and Na excretion rates in the metabolic syndrome

“…Circadian alterations in insulinemia may theoretically influence the circadian pattern of W-ExcR. Indeed, the epithelium of several nephron segments expresses the insulin receptor, which plays a role in water and electrolyte reabsorption (Li et al, 2012;Tiwari et al, 2008;Vidotti et al, 2008).…”

Resistance to insulin and kidney disease in the cardiorenal metabolic syndrome; role for angiotensin II

“…In contrast, renal tubule epithelial cell specific knockout of insulin receptor in mice result in impairment of sodium excretion, decreased urinary Nox excretion and hypertension especially in setting of metabolic syndrome (Tiwari 2008). Moreover, in this animal model decrease in Nox excretion was likely the result of decreased NO production and/or increased oxidative stress (Li 2012). …”

“…Thereby, insulin has a central and complicated role in kidney tissue remodeling through regulation of tubulointerstitial fibrosis and glomerular filtration barrier injury and in kidney function through its regulation of receptor signaling (Chen 2004; Anderson 1996; Welsh 2010; Li 2012). …”