Metabolic acidosis often accompanies low glomerular filtration rate and induces secretion of endothelin, which in turn might mediate kidney injury. Here we tested whether treatment of metabolic acidosis in patients with low glomerular filtration rate reduced the progression of kidney disease. Fifty-nine patients with hypertensive nephropathy and metabolic acidosis had their blood pressure reduced with regimens that included angiotensin-converting enzyme inhibition. Thirty patients were then prescribed sodium citrate, and the remaining 29, unable or unwilling to take sodium citrate, served as controls. All were followed for 24 months with maintenance of their blood pressure reduction. Urine endothelin-1 excretion, a surrogate of kidney endothelin production, and N-acetyl-beta-D-glucosaminidase, a marker of kidney tubulointerstitial injury, were each significantly lower, while the rate of estimated glomerular filtration rate decline was significantly slower. The estimated glomerular filtration rate was statistically higher after 24 months of sodium citrate treatment compared to the control group. Hence it appears that sodium citrate is an effective kidney-protective adjunct to blood pressure reduction and angiotensin-converting enzyme inhibition.
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. tal nephron acidification (1,2) through endothelindependent mechanisms (3). Dietary intake of acidproducing protein also increases distal nephron acidification (4,5) by mechanisms that are also endothelin dependent (5). In the latter studies, augmented distal nephron acidification was due to an endothelin-mediated increase in both Na ϩ /H ϩ exchange and H ϩ -ATPase activity (5). Endothelin stimulates Na ϩ /H ϩ exchange in vitro (6 -8), but no studies report that endothelin increases in vitro H ϩ -ATPase activity. Consequently, endothelin might stimulate H ϩ -ATPase activity indirectly given the many endocrine alterations induced by a systemic acid challenge, including stimulation of the reninangiotensin-aldosterone axis (9,10). Because increased dietary protein increases serum aldosterone (11), aldosterone increases distal nephron H ϩ -ATPase activity (12), and endothelin infusion increases aldosterone secretion in vivo (13,14), the present studies tested the hypothesis that the endothelin-mediated increase in distal nephron H ϩ -ATPase activity induced by acidproducing dietary protein is due to increased aldosterone activity. Materials and Methods Animals and Diet ProtocolMale and female Munich-Wistar rats (Harlan Sprague-Dawley, Houston, TX; 200 to 220 g) ate standard rat chow (Prolab RMH 2500 with 23% protein) for 1 wk, then ate a custom minimum electrolyte diet with protein as purified high-nitrogen casein (ICN Nutritional Biochemicals, Cleveland, OH) for 3 wk. High protein (HiPro) and control (CON) rats ate 50 and 20% protein, respectively. In preliminary studies, similar-weight rats ate 24.6 Ϯ 0.9 and 27.1 Ϯ 1.2 g/d, respectively (n ϭ 4, P ϭ 0.15), so all rats received 24 g/d diet to ensure similar and complete intake. Some ingested bosentan (Actelion, Allschwil, Switzerland), a nonpeptide endothelin A/B receptor antagonist (15), mixed with study diet (100 mg/kg body wt per d). This oral dose blocks action of pressor doses of intravenous big endothelin-1 (ET-1) for Ͼ24 h (15). Others ingested spironolactone (400 mg/kg body wt per d) dissolved in olive oil and mixed with diet. This oral dose is in excess of that required for virtually complete mineralocorticoid receptor blockade in vivo (16). All drank distilled H 2 O ad libitum. Urine Net Acid and ET-1 ExcretionWe measured daily urine net acid excretion (NAE) (17) and ET-1 (3) in a 24-h sample collected as described (5) from eight each of HiPro and CON rats in metabolic cages. We examined the effect of endothelin and aldosterone receptor blockade with bosentan and spironolactone, respectively, on urine NAE in paired and separate gr...
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 HCO 3 reabsorption by in vivo microperfusion (37.8 Ϯ 3.2 versus 16.6 Ϯ 1.5 pmol/mm per min; P Ͻ 0.001) as a result of higher H ϩ secretion (41.3 Ϯ 4.0 versus 23.0 Ϯ 2.1 pmol/mm per min; P Ͻ 0.002) and lower HCO 3 secretion (Ϫ3.5 Ϯ 0.4 versus Ϫ6.4 Ϯ 0.8 pmol/mm per min; P Ͻ 0.001). Perfusion with H ϩ inhibitors support that increased H ϩ secretion was mediated by augmented Na ϩ /H ϩ exchange and H ϩ -ATPase activity without augmented H ϩ ,K ϩ -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 HCO 3 reabsorption (22.4 Ϯ 1.9 versus 37.8 Ϯ 3.2 pmol/mm per min; P Ͻ 0.001) as a result of lower H ϩ secretion (28.4 Ϯ 2.4 versus 41.3 Ϯ 4.0 pmol/mm per min; P Ͻ 0.016) and higher HCO 3 secretion (Ϫ6.0 Ϯ 0.7 versus Ϫ3.5 Ϯ 0.4 pmol/mm per min; P Ͻ 0.006). The H ϩ inhibitors had no additional effect in HiPro ingesting bosentan, supporting that ET mediated the increased distal nephron Na ϩ /H ϩ exchange and H ϩ -ATPase activity in HiPro. Increased dietary protein augments distal nephron acidification that is mediated through an ET-sensitive increase in Na ϩ /H ϩ exchange and H ϩ -ATPase activity.The routine acid challenges to systemic acid-base status faced by humans are modest compared with the large acid loads administered to animals in most experimental protocols. Augmented distal rather than proximal nephron acidification is the predominant renal regulatory response in experimental animals to modest dietary acid loads induced by acid-producing mineral salts (1,2). Augmented distal nephron acidification induced by dietary acid is mediated by multiple mechanisms, including (1) increased net HCO 3 reabsorption (3), consistent with increased H ϩ secretion; (2) reduced HCO 3 delivery to the terminal distal nephron (4) that facilitates NH 4 ϩ secretion (5) and permits secreted H ϩ to effect acid excretion rather than HCO 3 reclamation; and (3) decreased distal nephron HCO 3 secretion (1) mediated by endogenous endothelins (ET) (2).In contrast with the acid-producing mineral salts that are most commonly used to induce an acid challenge in experimental protocols, increased intake of dietary protein that contains acid-producing amino acids constitutes the acid challenge that humans more routinely face. Intake of acid-producing amino acids increases systemic acid production and urine net acid excretion (6), but its effect on distal nephron acidification or its hormonal and/or transport mediators are not known. Recognizing that ET ...
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