Dietary protein induces endothelin-mediated kidney injury through enhanced intrinsic acid production

Dietary protein as casein ( CAS) augments intrinsic acid production, induces endothelin-mediated kidney acidification, and promotes kidney injury. We tested the hypothesis that dietary CAS induces endothelin-mediated kidney injury through augmented intrinsic acid production. Munich-Wistar rats ate minimum electrolyte diets from age 8 to 96 weeks with 50 or 20% protein as either acid-inducing CAS or non-acid-inducing SOY. Urine net acid excretion and distal nephron net HCO3 reabsorption by in vivo microperfusion ( Net J(HCO3)) were higher in 50 than 20% CAS but not 50 and 20% SOY. At 96 weeks, 50% compared the 20% CAS had higher urine endothelin-1 excretion ( UET-1V) and a higher index of tubulo-interstitial injury ( TII) at pathology ( 2.25 +/- 0.21 vs 1.25 +/- 0.13 U, P < 0.03), but each parameter was similar in 50 and 20% SOY. CAS ( 50%) eating NaHCO3 to reduce intrinsic acid production had lower Net J(HCO3), lower UET-1V, and less TII. By contrast, 50% SOY eating dietary acid as ( NH4)(2)SO4 had higher Net J(HCO)3, higher UET-1V, and more TII. Endothelin A/B but not A receptor antagonism reduced Net J(HCO3) in 50% CAS and 50% SOY+( NH4)(2)SO4 animals. By contrast, endothelin A but not A/B receptor antagonism reduced TII in each group. The data support that increased intake of acid-inducing dietary protein induces endothelin B-receptor-mediated increased Net JHCO3 and endothelin A-receptor-mediated TII through augmented intrinsic acid production.