title: Reduced ENaC activity and blood pressure in mice with genetic knockout of the insulin receptor in the renal collecting duct.
abstract: To elucidate the role of the insulin receptor (IR) in collecting duct (CD), we bred mice with IR selectively deleted from CD principal cells using an aquaporin-2 promoter to drive Cre-recombinase expression. Young, adult male knockout (KO) mice had altered plasma and electrolyte homeostasis under high- (HS) and low-sodium (LS) diets, relative to wild-type (WT) littermates. One week of LS feeding led to a significant reduction in urine potassium (K(+)) and sodium (Na(+)) excretion in KO, and a reduction in the ratio of Na(+) to chloride (Cl(-)) in plasma, relative to WT. HS diet (1 wk) increased plasma K(+) and reduced urine Na(+) to Cl(-) ratio in the KO. Furthermore, KO mice had a significantly (P = 0.025) blunted natriuretic response to benzamil, an epithelial sodium channel (ENaC) antagonist. Western blotting of cortex homogenates revealed modestly, but significantly (∼15%), lower band density for the β-subunit of ENaC in the KO vs. WT mice, with no differences for the α- or γ-subunits. Moreover, blood pressure (BP), measured by radiotelemetry, was significantly lower in KO vs. WT mice under basal conditions (mmHg): 112 ± 5 (WT), 104 ± 2 (KO), P = 0.023. Chronic insulin infusion reduced heart rate in the WT, but not in the KO, and modestly reduced BP in the WT only. Overall, these results support a fundamental role for insulin through its classic receptor in the modulation of electrolyte homeostasis and BP.
authors.affiliation: Department of Medicine, Georgetown University, Washington, DC 20007, USA.
authors.forename: Lijun
authors.initials: L
authors.lastname: Li
authors.forename: R Mayuri
authors.initials: RM
authors.lastname: Garikepati
authors.forename: Susanna
authors.initials: S
authors.lastname: Tsukerman
authors.forename: Donald
authors.initials: D
authors.lastname: Kohan
authors.forename: James B
authors.initials: JB
authors.lastname: Wade
authors.forename: Swasti
authors.initials: S
authors.lastname: Tiwari
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Ecelbarger
mesh_terms: D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D004573:Electrolytes / Q000378:metabolism; D053503:Epithelial Sodium Channels / Q000172:deficiency* / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006706:Homeostasis / Q000502:physiology; D007328:Insulin / Q000494:pharmacology; D019426:Integrases / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D011972:Receptor, Insulin / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
chemical_list: D051399:Aquaporin 2; D004573:Electrolytes; D053503:Epithelial Sodium Channels; D007328:Insulin; C013407:benzamil; D000584:Amiloride; D011972:Receptor, Insulin; C045073:Cre recombinase; D019426:Integrases