Regulation of blood pressure, the epithelial sodium channel (ENaC), and other key renal sodium transporters by chronic insulin infusion in rats.
Hyperinsulinemia is associated with hypertension. Dysregulation of renal distal tubule sodium reabsorption may play a role. We evaluated the regulation of the epithelial sodium channel (ENaC) and the thiazide-sensitive Na-Cl cotransporter (NCC) during chronic hyperinsulinemia in rats and correlated these changes to blood pressure as determined by radiotelemetry. Male Sprague-Dawley rats ( approximately 270 g) underwent one of the following three treatments for 4 wk (n = 6/group): 1) control; 2) insulin-infused plus 20% dextrose in drinking water; or 3) glucose water-drinking (20% dextrose in water). Mean arterial pressures were increased by insulin and glucose (mmHg at 3 wk): 98 +/- 1 (control), 107 +/- 2 (insulin), and 109 +/- 3 (glucose), P < 0.01. Insulin (but not glucose) increased natriuretic response to benzamil (ENaC inhibitor) and hydrochlorothiazide (NCC inhibitor) on average by 125 and 60%, respectively, relative to control rats, suggesting increased activity of these reabsorptive pathways. Neither insulin nor glucose affected the renal protein abundances of NCC or the ENaC subunits (alpha, beta, and gamma) in kidney cortex, outer medulla, or inner medulla in a major way, as determined by immunoblotting. However, insulin and to some extent glucose increased apical localization of these subunits in cortical collecting duct principal cells, as determined by immunoperoxidase labeling. In addition, insulin decreased cortical "with no lysine" kinase (WNK4) abundance (by 16% relative to control), which may have increased NCC activity. Overall, insulin infusion increased blood pressure, and NCC and ENaC activity in rats. Increased apical targeting of ENaC and decreased WNK4 expression may be involved.
Song
Jian
J
Division of Endocrinology and Metabolism, Department of Medicine, Georgetown Univ., 4000 Reservoir Rd. 233 NW, Washington, DC 20057-1412, USA.
Hu
Xinqun
X
Riazi
Shahla
S
Tiwari
Swasti
S
Wade
James B
JB
Ecelbarger
Carolyn A
CA
D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D053503:Epithelial Sodium Channels; D006946:Hyperinsulinism / Q000150:complications; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000493:pharmacokinetics; D015222:Sodium Channels / Q000502:physiology*; D049992:Sodium Chloride Symporters / Q000502:physiology
D053503:Epithelial Sodium Channels; D007004:Hypoglycemic Agents; D007328:Insulin; D015222:Sodium Channels; D049992:Sodium Chloride Symporters; D012964:Sodium; C499025:Wnk4 protein, rat; D017346:Protein Serine-Threonine Kinases