Role of the collecting duct insulin receptor in fluid homeostasis in response to high‐ and low‐NaCl diets.

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Recently we showed reduced ENaC activity and blood pressure (BP) in mice lacking the insulin receptor (IR) in collecting duct (CD) principal cells by aquaporin‐2 promoter targeted Cre‐recombinase knockout (KO). Here we test whether KO mice have impaired ability to maintain homeostasis in response to chronic high‐ (HS, 5% NaCl) or low‐ (LS, 0.02% Na+) sodium diets. After 1‐week feeding, LS KO mice had 20% reduced 24‐hr urine volume, as compared to WT, and significantly reduced ratios of Na+ to Cl− and K+ in urine. Likewise, the Na+ to Cl− ratio was reduced in HS KO (relative to WT). BP (by telemetry) did not change in either genotype with HS diet, but decreased slightly by LS in both genotypes. Four weeks of HS or LS diet resulted in KO mice being modestly, but significantly (p = 0.046) lighter than WT littermates (~10%). HS diet increased kidney weight in both genotypes (~17%). Western blotting was used to evaluate principal cell proteins involved in electrolyte homeostasis. LS diet led to an increase in the α‐subunit of the epithelial sodium channel (ENaC) and the lower (75‐kDa) band of γ‐ENaC; however, band densities did not differ between genotypes. Serum and glucorticoid‐regulated kinase (sgk‐1) was increased by HS, and to a significantly greater extent in the WT mice (p = 0.038). Overall, these studies support a role for the renal CD‐IR in electrolyte homeostasis with chronic adjustments in dietary NaCl. NIH DK082507.