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Decreases in blood pH activate NHE3, the proximal tubular apical membrane Na/H antiporter. In cultured renal epithelial cells, activation of the endothelin-B (ETB) receptor increases NHE3 activity. To examine the role of the ETB receptor in the response to acidosis in vivo, the present studies examined ETB receptor-deficient mice, rescued from neonatal lethality by expression of a dopamine β-hydroxylase promoter/ETB receptor transgene (Tg/Tg:ETB−/− mice). In proximal tubule suspensions from Tg/Tg:ETB+/− mice, 10−8 M endothelin-1 (ET-1) increased NHE3 activity, but this treatment had no effect on tubules from Tg/Tg:ETB−/− mice. Acid ingestion for 7 days caused a greater decrease in blood HCO3− concentration in Tg/Tg:ETB−/− mice compared with Tg/Tg:ETB+/+ and Tg/Tg:ETB+/− mice. Whereas acid ingestion increased apical membrane NHE3 by 42-46% in Tg/Tg:ETB+/+ and Tg/Tg:ETB+/− mice, it had no effect on NHE3 in Tg/Tg:ETB−/− mice. In C57BL/6 mice, excess acid ingestion increased renal cortical preproET-1 mRNA expression 2.4-fold and decreased preproET-3 mRNA expression by 37%. On a control diet, Tg/Tg:ETB−/− mice had low rates of ammonium excretion, which could not be attributed to an inability to acidify the urine, as well as hypercitraturia, with increased titratable acid excretion. Acid ingestion increased ammonium excretion, citrate absorption, and titratable acid excretion to the same levels in Tg/Tg:ETB−/− and Tg/Tg:ETB+/+ mice. In conclusion, metabolic acidosis increases ET-1 expression, which increases NHE3 activity via the ETB receptor.