Role of angiotensin II in the enhancement of ammonia production and secretion by the proximal tubule in metabolic acidosis

Abstract

Nagami GT. Role of angiotensin II in the enhancement of ammonia production and secretion by the proximal tubule in metabolic acidosis. Am J Physiol Renal Physiol 294: F874-F880, 2008. First published February 20, 2008 doi:10.1152/ajprenal.00286.2007.-Acidosis and angiotensin II stimulate ammonia production and transport by the proximal tubule. We examined the modulatory effect of the type 1 angiotensin II receptor blocker losartan on the ability of metabolic acidosis to stimulate ammonia production and secretion by mouse S2 proximal tubule segments. Mice given NH 4Cl for 7 days developed metabolic acidosis (low serum bicarbonate concentration) and increased urinary excretion of ammonia. S2 tubule segments from acidotic mice displayed higher rates of ammonia production and secretion compared with those from control mice. However, when losartan was coadministered in vivo with NH 4Cl, both the acidosisinduced increase in urinary ammonia excretion and the adaptive increase in ammonia production and secretion of microperfused S2 segments were largely blocked. In renal cortical tissue, losartan blocked the acid-induced increase in brush-border membrane NHE3 expression but had no effect on the acid-induced upregulation of phosphate-dependent glutaminase or phosphoenolpyruvate carboxykinase 1 in cortical homogenates. Addition of angiotensin II to the microperfusion solution enhanced ammonia secretion and production rates in tubules from NH 4Cl-treated and control mice in a losartaninhibitable manner. These results demonstrate that a 7-day acid challenge induces an adaptive increase in ammonia production and secretion by the proximal tubule and suggest that during metabolic acidosis, angiotensin II signaling is necessary for adaptive enhancements of ammonia excretion by the kidney and ammonia production and secretion by S2 proximal tubule segments, as mediated, in part, by angiotensin receptor-dependent enhancement of NHE3 expression. ammonia transport; ammoniagenesis; acid-base physiology; losartan; sodium-hydrogen exchanger A MAJOR WAY that the kidneys defend the body against the introduction of excess acid is through the production and excretion of total ammonia (tNH 3 ϭ NH 3 ϩ NH 4 ϩ ) (15,21,29,33,36). The proximal tubule is the major site of this response to acid challenges, increasing its rates of tNH 3 production and secretion and generating new bicarbonate formation (8,26). We previously demonstrated that chronic metabolic acidosis in vivo stimulates tNH 3 production and secretion by mouse S2 proximal tubule segments (24). The increased rates of ammoniagenesis persist even after the tubule is removed from the acidotic animal and assayed in vitro under normal pH conditions. Such adaptive changes result from the induction of key ammoniagenic enzymes (5, 37).In our previous study, short-term (18-h) acid challenges induced an adaptive enhancement in the rate of tNH 3 secretion, but not production in an angiotensin II (ANG II)-dependent manner (22). Giving the acid challenge concurrently with a type 1 ANG II (AT1) r...

Proximal tubule-specific glutamine synthetase deletion alters basal and acidosis-stimulated ammonia metabolism

“…Apical NHE3 is believed to be an important mechanism of PT apical ammonia secretion (30,42,43). NHE3 expression was not altered significantly as a result of PT-GS-KO in either the cortex or outer stripe of the outer medulla either under basal conditions or after acid loading (Fig.…”

“…Several studies have suggested that apical NHE3 is the primary mechanism of PT ammonia secretion (30,42,43). However, other studies have suggested that mechanisms other than NHE3 are important (51,52), and a recent study showed that PT-specific NHE3 deletion did not alter either basal or acidosis-stimulated renal ammonia excretion (37).…”

Acid loading in vivo and low pH in culture increase angiotensin receptor expression: enhanced ammoniagenic response to angiotensin II

“…After mice were given 0.3 M NH 4Cl in 2% sucrose water or 2% sucrose water alone for 18 h, renal cortical tissue was dissected from two mouse kidneys, and homogenates were prepared by homogenization in mannitol buffer using a rotator-stator homogenizer, followed by slow-speed centrifugation to remove debris, as described previously (24). After an aliquot for total protein processing was taken, the remainder of the supernatant of the crude homogenate was used to prepare BBMs (24) as described by Booth and Kenny (1) and modified by Karniski et al (12,13).…”

“…When tested in vitro, ANG II has concentration-dependent effects on tNH 3 production and transport by the proximal tubule (19,20). The stimulatory effect of ANG II on tNH 3 production rates is mediated by type 1 ANG II (AT 1 ) receptors, and this stimulatory effect is enhanced in proximal tubule segments derived from acid-loaded mice (22)(23)(24).Using in vitro microperfused mouse proximal tubules, we previously demonstrated that a short-term (18 h) NH 4 Cl acid challenge in vivo resulted in an increased stimulatory effect of ANG II on tNH 3 production (22). Nevertheless, it was unclear whether upregulation of the systemic renin-angiotensin system with acid loading (9, 10, 27) was responsible for the increased ammoniagenic response to ANG II of proximal tubule segments isolated from acid-loaded mice.…”

“…When tested in vitro, ANG II has concentration-dependent effects on tNH 3 production and transport by the proximal tubule (19,20). The stimulatory effect of ANG II on tNH 3 production rates is mediated by type 1 ANG II (AT 1 ) receptors, and this stimulatory effect is enhanced in proximal tubule segments derived from acid-loaded mice (22)(23)(24).…”