Increased endothelin activity mediates augmented distal nephron acidification induced by dietary protein

We tested the hypothesis that increased dietary protein augments distal nephron acidification through an endothelin-dependent mechanism. Munich-Wistar rats ate minimum electrolyte diets of 50% (HiPro) and 20% (CON) casein-provided protein, the latter comparable to standard chow. HiPro vs. CON had higher distal nephron H+ secretion (41.3 +/- 4.0 vs. 23.0 +/- 2.1 pmol/mm.min, p < 0.002) mediated by augmented Na+/H+ exchange and H(+)-ATPase activity. Renal cortex of HiPro vs. CON had higher ET-1 addition to microdialysate and higher ET-1 mRNA, consistent with increased renal ET-1 production. Bosentan, an endothelin A/B receptor antagonist, decreased HiPro distal nephron H+ secretion (28.4 +/- 2.4 vs. 41.3 +/- 4.0 pmol/mm.min, p < 0.016) through decreased Na+/H+ exchange and decreased H(+)-ATPase activity. Increased dietary protein augments distal nephron acidification through an endothelin-sensitive increase in Na+/H+ exchange and H(+)-ATPase activity, supporting an endothelin role in the distal nephron response to this common challenge to acid-base status.