The Renal Aldosterone‐Endothelin Feedback System (RAES) Controls Total Na Balance and Blood Pressure

Aldosterone increases blood pressure (BP) by stimulating sodium (Na) reabsorption in the collecting duct (CD) and, by negative feedback, stimulates CD endothelin‐1 (ET‐1) that acts to inhibit Na and water reabsorption. We tested the hypothesis that a renal aldosterone‐endothelin feedback system (RAES) regulates Na balance and BP by comparing the effect of a high NaCl diet (2% gelled diet with saline to drink) and mineralocorticoid stimulation in wild‐type mice (WT) and CD‐specific ET‐1 knockout mice (KO). Metabolic balance and radiotelemetric BP were measured before and after treatment with desoxycorticosterone pivalate (DOCP, 0.07mg/g, IM). KO mice consumed more HS diet and saline and had greater urine output than WT. Before DOCP, the KO mice, but not WT, increased fluid balance, body weight (BW), and BP. WT mice did not increase fluid balance, BW, or BP until after DOCP treatment. DOCP further increased systolic BP in the KO. After DOCP, KO mice exhibited greater positive electrolyte and fluid balance and BW than WT. Unlike WT, KO mice failed to respond acutely to DOCP treatment with transient positive Na balance and subsequent return to neutral Na balance (mineralocorticoid escape). Thus, the absence of RAES impairs renal response to Na loading, which results in abnormal fluid and electrolyte handling when challenged with a HS diet and DOCP treatment. We conclude that 1) CD expressed ET‐1 functions as a principal mechanism for mineralocorticoid escape; 2) disruption of RAES prevents renal compensation to, and escape from, the chronic effects of mineralocorticoids on electrolyte balance.