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

Abstract

Renal control of effective circulating volume is key for circulatory performance. When renal Na+ excretion is inadequate, blood pressure rises and serves as a homeostatic signal to drive natriuresis to re-establish effective circulating volume (ECV). Recognizing that hypertension involves both renal and vascular dysfunction, this report concerns proximal tubule Na+/H+ exchanger 3 (PT NHE3) regulation during acute and chronic hypertension. NHE3 is distributed in tall microvilli (MV) in the PT where it reabsorbs a significant fraction of the filtered Na+. NHE3 redistributes, in the plane of the MV membrane, between the MV body, where NHE3 is active, and MV base where NHE3 is less active. High salt diet and acute hypertension both retract NHE3 to the base and reduce PT Na+ reabsorption independent of a change in abundance. The renin angiotensin system provokes NHE3 redistribution independent of blood pressure: the ACE inhibitor captopril redistributes NHE3 to the base and subsequent AngII infusion returns NHE3 to the body of the microvilli and restores reabsorption. Chronic AngII infusion presents simultaneous AngII stimulation and hypertension: NHE3 remains in the body of the MV, due to the high local AngII 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 PT AngII receptors, IL-17A or IFN-γ expression) exhibit reduced local AngII accumulation and inflammation and larger decreases in NHE3 abundance which improve the pressure natriuresis responses and reduces the need for elevated BP to facilitate circulating volume balance.

Sexual Dimorphic Pattern of Renal Transporters and Electrolyte Homeostasis

“…Maintaining a reserve pool of NHE3 at the base of the villi could provide a mechanism to rapidly increase Na + reabsorption by redistribution of NHE3 into the body of the microvilli (e.g., during pregnancy, lactation, AngII stimulation), a hypothesis that remains to be tested. 3,21 Likewise, the transporter responses of females to stimuli that, in males, redistribute NHE3 and NaPi2 to the microvillar base (acute hypertension, ACE inhibition, or PTH) 21 or into the microvilli (AngII, sympathetic stimulation), remain to be determined. Although specific probes for AngII receptors are lacking, we assessed abundance of angiotensin-converting enzyme (ACE1) and angiotensin-converting enzyme 2 (ACE2) in cortical homogenates of both sexes of rats.…”

“…7 Pressure natriuresis, directly related to the BP set point, is ultimately a function of sodium transporter activity along the nephron. [19][20][21] Studies comparing transporter abundance in both sexes concur that females have higher distal NCC abundance and activation by phosphorylation (NCCp) due to ovarian hormones and prolactin, [22][23][24][25] but activated NCC does not explain lower BP. Previous studies of Na + transporter regulation that include both sexes indicate animal-and straindependent differences.…”

Impact of angiotensin II-mediated stimulation of sodium transporters in the nephron assessed by computational modeling

“…The results of the 3-day ANG II simulations indicate that transporter abundance is not always a proxy for transporter flux. Activity per transporter can be modulated by local signals (nitric oxide, 20-HETE, dopamine, superoxide) that can override changes in transporter pool size (5,11), for example, by stimulating trafficking into and out of active domains in the plasma membrane (24). Lack of correlation between overall abundance and transport capacity is also evident in ENaC activation mediated by subunit cleavage, which is associated with apparent decreases in pool size of full-length subunits with the appearance of pools of smaller subunits (43).…”

Understanding sex differences in long-term blood pressure regulation: insights from experimental studies and computational modeling

“…Females tend to exhibit a leftward shift in the pressurenatriuresis relation relative to males, i.e., females excrete the same amount of Na ϩ as males, but at lower arterial pressure under the same physiological conditions (28,37). Pressurenatriuresis responses encompass multiple levels of Na ϩ transporter regulation (51,52) and are substantially modulated by the RAAS (54).…”