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

• Published in: American journal of physiology. Renal physiology Vol. 317; no. 6; pp. F1656 - F1668
• Main Authors: Edwards, Aurélie, McDonough, Alicia A
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.12.2019
• Subjects: Abundance; Angiotensin; Angiotensin II; Angiotensin II - pharmacology; Animals; Blood pressure; Blood Pressure - drug effects; Computer applications; Computer Simulation; Cortex; Creatinine; Creatinine - metabolism; Epithelial Sodium Channels; Excretion; Kidney Medulla - drug effects; Kidney Medulla - metabolism; Kidney Tubules, Proximal - drug effects; Kidney Tubules, Proximal - metabolism; Lithium - urine; Male; Membrane Transport Proteins - metabolism; Na+/H+-exchanging ATPase; Natriuresis - drug effects; Nephrons - metabolism; Potassium - metabolism; Rats; Reabsorption; Sodium; Sodium - metabolism; Sodium - urine; Sodium-Hydrogen Exchanger 3 - metabolism; Solute Carrier Family 12, Member 1 - metabolism; Urine; mathematical model; kidney; pressure natriuresis; hypertension
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00335.2019

Angiotensin II (ANG II) raises blood pressure partly by stimulating tubular Na reabsorption. The effects of ANG II on tubular Na transporters (i.e., channels, pumps, cotransporters, and exchangers) vary between short-term and long-term exposure. To better understand the physiological impact, we used a computational model of transport along the rat nephron to predict the effects of short- and long-term ANG II-induced transporter activation on Na and K reabsorption/secretion, and to compare measured and calculated excretion rates. Three days of ANG II infusion at 200 ng·kg ·min is nonpressor, yet stimulates transporter accumulation. The increase in abundance of Na /H exchanger 3 (NHE3) or activated Na -K -2Cl cotransporter-2 (NKCC2-P) predicted significant reductions in urinary Na excretion, yet there was no observed change in urine Na . The lack of antinatriuresis, despite Na transporter accumulation, was supported by Li and creatinine clearance measurements, leading to the conclusion that 3-day nonpressor ANG II increases transporter abundance without proportional activation. Fourteen days of ANG II infusion at 400 ng·kg ·min raises blood pressure and increases Na transporter abundance along the distal nephron; proximal tubule and medullary loop transporters are decreased and urine Na and volume output are increased, evidence for pressure natriuresis. Simulations indicate that decreases in NHE3 and NKCC2-P contribute significantly to reducing Na reabsorption along the nephron and to pressure natriuresis. Our results also suggest that differential regulation of medullary (decrease) and cortical (increase) NKCC2-P is important to preserve K while minimizing Na retention during ANG II infusion. Lastly, our model indicates that accumulation of active Na -Cl cotransporter counteracts epithelial Na channel-induced urinary K loss.