Preincubation in acid medium increases Na/H antiporter activity in cultured renal proximal tubule cells.

Horie, Shigeo; Moe, Orson W.; Tejedor, Alberto; Alpern, Robert J.

doi:10.1073/pnas.87.12.4742

Cited by 78 publications

(84 citation statements)

References 31 publications

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“…Thus, the tubule is exposed continuously to a newly generated solution. Alpern and colleagues showed that cultured PT cells that were subjected for 2 d to either metabolic or respiratory acidosis responded by increasing their activity of Na-H exchange, a process that requires new protein synthesis (111). Moreover, this effect, as well as increased expression of NHE3 mRNA, is blocked by overexpressing Csk (112), a natural inhibitor of src kinases.…”

Section: Ooe Co 2 /Hco 3 ϫ Solutionsmentioning

confidence: 99%

Acid-Base Transport by the Renal Proximal Tubule

Boron

2006

Journal of the American Society of Nephrology

170

144

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One of the major tasks of the renal proximal tubule is to secrete acid into the tubule lumen, thereby reabsorbing approximately 80% of the filtered HCO 3 ؊ as well as generating new HCO 3 ؊ for regulating blood pH. This review summarizes the cellular and molecular events that underlie four major processes in HCO 3 ؊ reabsorption. The first is CO 2 entry across the apical membrane, which in large part occurs via a gas channel (aquaporin 1) and acidifies the cell. The second process is apical H ؉ secretion via Na-H exchange and H ؉ pumping, processes that can be studied using the NH 4 ؉ prepulse technique. The third process is the basolateral exit of HCO 3 ؊ via the electrogenic Na/HCO 3 co-transporter, which is the subject of at least 10 mutations that cause severe proximal renal tubule acidosis in humans. The final process is the regulation of overall HCO 3 ؊ reabsorption by CO 2 and HCO 3 ؊ sensors at the basolateral membrane. Together, these processes ensure that the proximal tubule responds appropriately to acute acid-base disturbances and thereby contributes to the regulation of blood pH.

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Section: Ooe Co 2 /Hco 3 ϫ Solutionsmentioning

confidence: 99%

Acid-Base Transport by the Renal Proximal Tubule

Boron

2006

Journal of the American Society of Nephrology

170

144

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“…Chronic acidosis causes several metabolic alterations in the renal proximal tubule, including increased H ϩ secretion (1,5), ammonia synthesis (6), and citrate reabsorption (6,7). These changes in tubule function are associated with changes in the activities of a number of proteins, including the apical membrane Na ϩ /H ϩ antiporter (7), glutaminase and glutamate dehydrogenase (8), and phosphoenolpyruvate carboxykinase (9), which may affect intracellular substrate availability for protein turnover, amino acid metabolism and/or transport, and gluconeogenesis.…”

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confidence: 99%

Kidney Protein Dynamics and Ammoniagenesis in Humans with Chronic Metabolic Acidosis

Garibotto

Asioli²,

Robaudo³

et al. 2004

Journal of the American Society of Nephrology

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Abstract. To evaluate the effects of chronic metabolic acidosis on protein dynamics and amino acid oxidation in the human kidney, a combination of organ isotopic ( 14 C-leucine) and mass-balance techniques in 11 subjects with normal renal function undergoing venous catheterizations was used. Five of 11 studies were performed in the presence of metabolic acidosis. In subjects with normal acid-base balance, kidney protein degradation was 35% to 130% higher than protein synthesis, so net protein leucine balance was markedly negative. In acidemic subjects, kidney protein degradation was no different from protein synthesis and was significantly lower (P Ͻ 0.05) than in controls. Kidney leucine oxidation was similar in both groups. Urinary ammonia excretion and total ammonia production were 186% and 110% higher, respectively, and more of the ammonia that was produced was shifted into urine (82% versus 65% in acidemic subjects versus controls). In all studies, protein degradation and net protein balance across the kidney were inversely related to urinary ammonia excretion and to the partition of ammonia into urine, but not to total ammonia production, arterial pH, , urinary flow, the uptake of glutamine by the kidney, or the ammonia released into the renal veins. The data show that response of the human kidney to metabolic acidosis includes both changes in amino acid uptake and suppression of protein degradation. The latter effect, which is likely induced by the increase in ammonia excretion and partition into the urine, is potentially responsible for kidney hypertrophy.Both in vitro and in vivo studies in animals have shown that metabolic acidosis causes several biochemical and morphologic changes in tubule cells, which are ultimately associated with kidney hypertrophy (1,2). Protein synthesis and degradation, the determinants of protein metabolism, are key factors in the hypertrophy process. However, information regarding the signals and mechanisms by which metabolic acidosis might cause kidney hypertrophy is still incomplete, and whether these effects take place in the human kidney is unknown. A further complicating element is that the effects of acidosis on protein turnover rates vary in different tissue types, with catabolic events occurring in peripheral tissues and splanchnic organs (3,4).Chronic acidosis causes several metabolic alterations in the renal proximal tubule, including increased H ϩ secretion (1,5), ammonia synthesis (6), and citrate reabsorption (6,7). These changes in tubule function are associated with changes in the activities of a number of proteins, including the apical membrane Na ϩ /H ϩ antiporter (7), glutaminase and glutamate dehydrogenase (8), and phosphoenolpyruvate carboxykinase (9), which may affect intracellular substrate availability for protein turnover, amino acid metabolism and/or transport, and gluconeogenesis. It has been shown that in tubule epithelial cells, the associated increase in ammonia production, rather than the acidosis per se, is responsible for favoring tubular hyper...

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“…NHE1 has been shown to be stimulated by acid in both animals and cell culture but this is unlikely to be related to transepithelial transport of H + equivalents. [44][45][46] Chronic adaptation of NHE3 has been described in both the proximal tubule (increased NHE3 activity and protein) and TAL (increased NHE3 protein and transcript) in animals given a sufficient acid load to chronically suppress serum [HCO 3 − ]. 36,[47][48][49][50][51][52][53] Presently it is unclear whether the signals and mechanisms responsible for increased NHE3 are the same for the proximal tubule and TAL.…”

Section: Adaptation To Metabolic Acidosismentioning

confidence: 99%

Na+/H+ Exchangers in Renal Regulation of Acid-Base Balance

Bobulescu

Moe

2006

Seminars in Nephrology

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The kidney plays key roles in extracellular fluid pH homeostasis by reclaiming bicarbonate (HCO 3 − ) filtered at the glomerulus and generating the consumed HCO 3 − by secreting protons (H + ) into the urine (renal acidification). Sodium-proton exchangers (NHEs) are ubiquitous transmembrane proteins mediating the countertransport of Na + and H + across lipid bilayers. In mammals, NHEs participate in the regulation of cell pH, volume, and intracellular sodium concentration, as well as in transepithelial ion transport. Five of the 10 isoforms (NHE1-4 and NHE8) are expressed at the plasma membrane of renal epithelial cells. The best-studied isoform for acid-base homeostasis is NHE3, which mediates both HCO 3 − absorption and H + excretion in the renal tubule. This article reviews some important aspects of NHEs in the kidney, with special emphasis on the role of renal NHE3 in the maintenance of acid-base balance.Keywords sodium/hydrogen exchange; renal acidification; bicarbonate absorption The free hydrogen ion (H + ) concentration in body fluids is regulated exquisitely around 40 nmol/L (pH 7.40) whereas H + flux through the body greatly exceeds this magnitude. In a 70-kg human being at a basal state, normal metabolic and dietary acid production rate is about 50 to 70 mmoles/d and respiratory volatile acid production at the basal state is around 15,000 mmoles/d, with peak production at maximal exercise reaching 200 mmoles/min. The flux of H + through the organism over 24 hours is 8 orders of magnitude greater than the total pool of free H + in total body water (<2 μmoles). This remarkable homeostatic feat is accomplished by concerted efforts of extracellular and intracellular buffers, highly efficient ventilatory responses, metabolic functions of the liver, and renal ammoniagenic and solute transport mechanisms. For excretion of nonvolatile acid and base loads, the kidney assumes the pivotal role.A filtration-reabsorption nephron bears an exorbitant burden of having to reclaim a vast amount of valuable solutes indiscriminately dispensed in the filtrate; one of which of course is the approximately 4,000 mmoles of bicarbonate (HCO 3 − ) per day. The luminal acid disequilibrium pH implies that the predominant mode of HCO 3 − absorption involves H + secretion, although a small concomitant degree of direct HCO 3 − reabsorption cannot be excluded. 1 Two points are noteworthy. First, complete reclamation of the approximately 4,000 mmoles of filtered HCO 3 − forestalls a physiologic disaster but does not lead to net acid secretion. Further elaboration of H + into the urine is necessary. Second, whether the organism is catering to the The era of phenomenologic analysis was supplemented by gene-and protein-specific reagents when the first mammalian NHE was cloned by Sardet et al. 7 The relationship between mammalian NHE genetic sequence and those from a multitude of organisms is shown in Fig 2. Na + /H + exchange across lipid bilayers and proteins that sustain this function are universal in prokaryotic, animal, and...

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Preincubation in acid medium increases Na/H antiporter activity in cultured renal proximal tubule cells.

Cited by 78 publications

References 31 publications

Acid-Base Transport by the Renal Proximal Tubule

Acid-Base Transport by the Renal Proximal Tubule

Kidney Protein Dynamics and Ammoniagenesis in Humans with Chronic Metabolic Acidosis

Na+/H+ Exchangers in Renal Regulation of Acid-Base Balance

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