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

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), 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 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 stimulation followed by compensatory reduction in proximal nephron T and accompanying adjustments to limit excessive K secretion. 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.