Angiotensin II hypertension along the female rat tubule: predicted impact on coupled transport of Na+ and K

Abstract

Chronic infusion of subpressor level of angiotensin II (ANG II) increases the abundance of Na⁺ transporters along the distal nephron, balanced by suppression of Na⁺ transporters along the proximal tubule and medullary thick ascending limb (defined as "proximal nephron"), which impacts K⁺ handling along the entire renal tubule. The objective of this study was to quantitatively assess the impact of chronic ANG II on the renal handling of Na⁺ and K⁺ in female rats, using a computational model of the female rat renal tubule. Our results indicate that the downregulation of proximal nephron Na⁺ reabsorption (T_Na), which occurs in response to ANG II-triggered hypertension, involves changes in both transporter abundance and trafficking. Our model suggests that substantial (∼30%) downregulation of active NHE3 in proximal tubule (PT) microvilli is needed to reestablish the Na⁺ balance at 2 wk of ANG II infusion. The 35% decrease in SGLT2, a known NHE3 regulator, may contribute to this downregulation. Both depression of proximal nephron T_Na and stimulation of distal ENaC raise urinary K⁺ excretion in ANG II-treated females, while K⁺ loss is slightly mitigated by cortical NKCC2 and NCC upregulation. Our model predicts that K⁺ excretion may be more significantly limited during ANG II infusion by ROMK inhibition in the distal nephron and/or KCC3 upregulation in the PT, which remain open questions for experimental validation. In summary, our analysis indicates that ANG II hypertension triggers a series of events from distal T_Na stimulation followed by compensatory reduction in proximal nephron T_Na and accompanying adjustments to limit excessive K⁺ secretion.NEW & NOTEWORTHY We used a computational model of the renal tubule to assess the impact of 2-wk angiotensin II (ANG II) infusion on the handling of Na⁺ and K⁺ in female rats. ANG II strongly stimulates distal Na⁺ reabsorption and K⁺ secretion. Simulations indicate that substantial downregulation of proximal tubule NHE3 is needed to reestablish Na⁺ balance at 2 wk. Proximal adaptations challenge K⁺ homeostasis, and regulation of distal NCC and specific K⁺ channels likely limit urinary K⁺ losses.

Keywords: hypertension; kidney; mathematical model; pressure natriuresis.