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

Nephrology Section, Medical and Research Services, Veterans Affairs Greater Los Angeles Healthcare System at West Los Angeles, Los Angeles; and Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California Submitted 25 June 2007 ; accepted in final form 13 February 2008 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 4 Cl 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 4 Cl, both the acidosis-induced 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 4 Cl-treated and control mice in a losartan-inhibitable 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 Address for reprint requests and other correspondence: G. T. Nagami, Nephrology Section 111L, VA Greater Los Angeles Healthcare System at West Los Angeles, 11301 Wilshire Blvd., Los Angeles, CA 90073 (e-mail: glenn.nagami{at}va.gov )