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Increased Endothelin Activity Mediates Augmented Distal Nephron Acidification Induced by Dietary Protein

Apurv Khanna^*, Jan Simoni, Callenda Hacker^*, Marie-Josée Duran and Donald E. Wesson^*,

Departments of *Internal Medicine, Surgery, and Physiology, Texas Tech University Health Sciences Center, Texas Tech University School of Medicine, Lubbock, Texas

Correspondence to Dr. Donald E. Wesson, Texas Tech University Health Sciences Center, Renal Section, 3601 Fourth Street, Lubbock, TX 79430. Phone: 806-743-3107; Fax: 806-743-3177; E-mail: donald.wesson{at}ttuhsc.edu

ABSTRACT. The hypothesis that increased dietary protein augments distal nephron acidification and does so through an endothelin (ET-1)-dependent mechanism was tested. Munich-Wistar rats that ate minimum electrolyte diets of 50% (HiPro) and 20% (CON) casein-provided protein, the latter comparable to standard diet, were compared. HiPro versus CON had higher distal nephron net HCO₃ reabsorption by in vivo microperfusion (37.8 ± 3.2 versus 16.6 ± 1.5 pmol/mm per min; P < 0.001) as a result of higher H⁺ secretion (41.3 ± 4.0 versus 23.0 ± 2.1 pmol/mm per min; P < 0.002) and lower HCO₃ secretion (–3.5 ± 0.4 versus –6.4 ± 0.8 pmol/mm per min; P < 0.001). Perfusion with H⁺ inhibitors support that increased H⁺ secretion was mediated by augmented Na⁺/H⁺ exchange and H⁺-ATPase activity without augmented H⁺,K⁺-ATPase activity. HiPro versus CON had higher levels of urine ET-1 excretion, renal cortical ET-1 addition to microdialysate in vivo, and renal cortical ET-1 mRNA, consistent with increased renal ET-1 production. Oral bosentan, an ET A/B receptor antagonist, decreased distal nephron net HCO₃ reabsorption (22.4 ± 1.9 versus 37.8 ± 3.2 pmol/mm per min; P < 0.001) as a result of lower H⁺ secretion (28.4 ± 2.4 versus 41.3 ± 4.0 pmol/mm per min; P < 0.016) and higher HCO₃ secretion (–6.0 ± 0.7 versus –3.5 ± 0.4 pmol/mm per min; P < 0.006). The H⁺ inhibitors had no additional effect in HiPro ingesting bosentan, supporting that ET mediated the increased distal nephron Na⁺/H⁺ exchange and H⁺-ATPase activity in HiPro. Increased dietary protein augments distal nephron acidification that is mediated through an ET-sensitive increase in Na⁺/H⁺ exchange and H⁺-ATPase activity.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673