Endothelin-Induced Increased Aldosterone Activity Mediates Augmented Distal Nephron Acidification as a Result of Dietary Protein

Abstract

The hypothesis that increased dietary protein augments distal nephron acidification through endothelin-mediated increased aldosterone activity was tested. Munich-Wistar rats were studied after 3 wk of diets with 50% high protein (HiPro) and 20% control (CON) casein-provided protein, the latter comparable to standard diet. HiPro versus CON rats had higher distal nephron H⁺ secretion by in vivo microperfusion as shown previously. Perfusion with inhibitors of Na⁺/H⁺ exchange (EIPA, 10⁻⁵ M), H⁺-ATPase (bafilomycin, 10⁻⁷ M), and H⁺-K⁺-ATPase (Sch 28080 [10⁻⁵ M] and ouabain [10⁻³ M]) support that higher Na⁺/H⁺ exchange and higher H⁺-ATPase but not higher H⁺-K⁺-ATPase activity mediated increased H⁺ secretion in HiPro rats. Oral bosentan, an endothelin A/B receptor antagonist, decreased distal nephron H⁺ secretion in HiPro rats as a result of reduced Na⁺/H⁺ exchange and H⁺-ATPase activity as shown previously by the authors’ laboratory. HiPro versus CON rats had higher plasma aldosterone (60.9 ± 5.9 versus 42.2 ± 4.4 pg/ml; P < 0.024) and higher urine aldosterone excretion (21.9 ± 3.9 versus 10.5 ± 2.8 ng/d; P < 0.04) in the absence but not presence of bosentan, consistent with endothelin-mediated increased aldosterone secretion. HiPro rats that did versus did not ingest the aldosterone antagonist spironolactone had lower distal nephron H⁺ secretion (29.2 ± 3.3 versus 42.1 ± 3.8 pmol/mm per min; P < 0.05) as a result of lower H⁺-ATPase activity without differences in Na⁺/H⁺ exchange or H⁺-K⁺-ATPase activity. The data support that dietary protein provided as casein increases distal nephron acidification through endothelin-stimulated Na⁺/H⁺ exchange and endothelin-stimulated aldosterone secretion that increases H⁺-ATPase activity.