ISN Forefronts Symposium 2015: Maintaining Balance Under Pressure—Hypertension and the Proximal Tubule

Abstract

Renal control of effective circulating volume (ECV) is key for circulatory performance. When renal sodium excretion is inadequate, blood pressure rises and serves as a homeostatic signal to drive natriuresis to re-establish ECV. Recognizing that hypertension involves both renal and vascular dysfunction, this report concerns proximal tubule sodium hydrogen exchanger 3 (NHE3) regulation during acute and chronic hypertension. NHE3 is distributed in tall microvilli (MV) in the proximal tubule, where it reabsorbs a significant fraction of the filtered sodium. NHE3 redistributes, in the plane of the MV membrane, between the MV body, where NHE3 is active, and the MV base, where NHE3 is less active. A high-salt diet and acute hypertension both retract NHE3 to the base and reduce proximal tubule sodium reabsorption independent of a change in abundance. The renin angiotensin system provokes NHE3 redistribution independent of blood pressure: The angiotensin-converting enzyme (ACE) inhibitor captopril redistributes NHE3 to the base and subsequent angiotensin II (AngII) infusion returns NHE3 to the body of the MV and restores reabsorption. Chronic AngII infusion presents simultaneous AngII stimulation and hypertension; that is, NHE3 remains in the body of the MV, due to the high local AngII level and inflammation, and exhibits a compensatory decrease in abundance driven by the hypertension. Genetically modified mice with blunted hypertensive responses to chronic AngII infusion (due to lack of the proximal tubule AngII receptors interleukin-17A or interferon-γ expression) exhibit reduced local AngII accumulation and inflammation and larger decreases in NHE3 abundance, which improves the pressure natriuresis response and reduces the need for elevated blood pressure to facilitate circulating volume balance.