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

Abstract

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 (U(ET-1)V) 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 U(ET-1)V, and less TII. By contrast, 50% SOY eating dietary acid as (NH4)2SO4 had higher Net J(HCO3), higher U(ET-1)V, and more TII. Endothelin A/B but not A receptor antagonism reduced Net J(HCO3) in 50% CAS and 50% SOY+(NH4)2SO4 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 J(HCO3) and endothelin A-receptor-mediated TII through augmented intrinsic acid production.

Role of endothelin-1 in renal regulation of acid-base equilibrium in acidotic humans

“…Consistent with this hypothesis, increased proximal tubule proton secretory capacity has been reported in response to metabolic acidosis and was shown to be mediated, at least in part, by increased activation of 18). Micropuncture studies in rat distal tubule have found that net acidification is also stimulated in these segments after a dietary acid load and that the increments are mediated in part by increased bosentan-inhibitable ET activity as modulated both by ET-induced apical Na/H exchange and by 33).While the authors did demonstrate higher plasma aldosterone levels in NaCl-restricted rats with higher acid loads from a high protein diet and that bosentan reduced the hyperaldosteronism, the micropuncture studies, including those showing an effect of sprironolactone, were performed with perfusate containing high concentrations of sodium (10). Since mineralocorticoid excess has no effect on renal or systemic acid-base equilibrium in NaCl-restricted acidotic dogs with high acid loads (9), it is unclear how the micropuncture mineralocorticoid effects demonstrated with sodium present are related to the bosentan effects on net acid excretion (NAE) and acid production reported in salt-restricted rats (11, 12).…”

“…Consistent with this hypothesis, increased proximal tubule proton secretory capacity has been reported in response to metabolic acidosis and was shown to be mediated, at least in part, by increased activation of ET-B (17,18). Micropuncture studies in rat distal tubule have found that net acidification is also stimulated in these segments after a dietary acid load and that the increments are mediated in part by increased bosentan-inhibitable ET activity as modulated both by ET-induced apical Na/H exchange and by ET-induced hyperaldosteronism (12,33).…”

“…Since mineralocorticoid excess has no effect on renal or systemic acid-base equilibrium in NaCl-restricted acidotic dogs with high acid loads (9), it is unclear how the micropuncture mineralocorticoid effects demonstrated with sodium present are related to the bosentan effects on net acid excretion (NAE) and acid production reported in salt-restricted rats (11,12). These reported studies in rats are confounded further by the observation that such NaCl-restricted rats treated with prolonged bosentan administration exhibit decreased endogenous acid production (decreased NAE), such that it is unclear whether bosentan causes a primary decrease in distal H ϩ secretion or whether the bosentan-induced decreased distal tubule H ϩ secretion (irrespective of the issue of sodium in perfusate) simply reflects the requirement for decreased renal H ϩ secretion to adjust to a decreased H ϩ load requiring excretion, to maintain H ϩ balance (12,33).…”

Drug therapies to delay the progression of chronic kidney disease

“…9,10 Possible mechanisms for the deleterious effect of acidosis on GFR may be the inadvertent pro-fibrotic effects of inducing regulatory mechanisms in the kidney, such as increased renal ammonium production, endothelin-A receptor activation and prolonged activation of the renin-angiotensin system. [11][12][13] A systematic review of six randomised controlled trials which administered oral sodium bicarbonate to pre-dialysis CKD patients, versus standard of care treatment or placebo, demonstrated a net improvement in GFR with alkali therapy, as well as reduced initiation of renal replacement and no safety concerns in the longer term. 14 Hence, this appears to be a safe and inexpensive therapy to delay progression of CKD.…”

Effect of metabolic acidosis on progression of chronic kidney disease

“…Others have suggested that the stimulation of new bicarbonate production in the kidney alkalinizes the interstitium thereby encouraging precipitation of calcium in the kidney and renal injury (6). Finally, studies in rats using the remnant kidney model of CKD indicated that the decline in GFR was mediated in part by the actions of excess aldosterone and endothelin, the latter acting via activation of endothelin A receptors (14,20,22).The studies cited above suggest that metabolic acidosis when present can contribute to progression of CKD, and therefore under these circumstances base treatment is warranted. However, the magnitude of hypobicarbonatemia present in patients with CKD is variable and some patients can actually have a normal serum [HCO 3 Ϫ ] even in the face of severe renal failure (19).…”