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• W2149162172 abstract "This month's discussion . . .The Journal Club focuses on an article entitled “Glucocorticoids Enhance Acid Activation of the Na+/H+ Exchanger 3 (NHE3)” (J Clin Invest 103: 429-435, 1999) by Patrice M. Ambühl, Xiaojing Yang, Yan Peng, Patricia A. Preisig, Orson W. Moe, and Robert J. Alpern.Glucocorticoids have an important role in the physiological response to systemic acidosis. This role is not only important from a physiological perspective, but also has important clinical implications. However, this interaction of glucocorticoids with acidosis has not been fully appreciated, except by a few groups. In the article under discussion, “Glucocorticoids Enhance Acid Activation of the Na+/H+ Exchanger 3 (NHE3),” Ambühl et al1Ambühl P Yang X Peng Y Preisig P Moe O Alpern R Glucocorticoids enhance acid activation of the Na+/H+ exchanger 3 (NHE3).J Clin Invest. 1999; 103: 429-435Crossref PubMed Scopus (45) Google Scholar explored the molecular mechanisms of this interaction in the proximal tubule.Adrenal insufficiency is often accompanied by metabolic acidosis, a result of decreased excretion of titratable acid and ammonium.2Sartorius O Calhoon D Pitts R Studies on the interrelationships of the adrenal cortex and renal ammonia excretion by the rat.Endocrinology. 1953; 52: 256-265Crossref PubMed Scopus (20) Google Scholar, 3Dubrovsky A Nair R Byers M Levine D Renal net acid excretion in the adrenalectomized rat.Kidney Int. 1981; 19: 516-528Crossref PubMed Scopus (32) Google Scholar Conversely, Cushing's syndrome frequently causes metabolic alkalosis. Although the effects of both these conditions have been attributed in part to distal tubule effects by mineralocorticoid receptors, glucocorticoids have important effects in the proximal tubule, particularly in response to acidosis. In adrenalectomized animals, glucocorticoids increase net acid excretion (ammonium plus titratable acid) more than aldosterone, despite a larger effect of the latter on reducing urine pH.4Wilcox C Cemerikic D Giebisch G Differential effects of acute mineralo- and glucocorticosteroid administration on renal acid elimination.Kidney Int. 1982; 21: 546-556Crossref PubMed Scopus (34) Google Scholar Importantly, in healthy animals or persons, metabolic acidosis results in a corticotropin-dependent increase in corticosteroids.2Sartorius O Calhoon D Pitts R Studies on the interrelationships of the adrenal cortex and renal ammonia excretion by the rat.Endocrinology. 1953; 52: 256-265Crossref PubMed Scopus (20) Google Scholar, 5Perez G Oster J Katz F Vaamonde C The effect of acute metabolic acidosis on plasma cortisol, renin activity and aldosterone.Hormone Res. 1979; 11: 12-21Crossref PubMed Scopus (40) Google Scholar, 6Welbourne T Acidosis activation of the pituitary-adrenal-renal glutaminase I axis.Endocrinology. 1976; 99: 1071-1079Crossref PubMed Scopus (48) Google Scholar In turn, the increase in glucocorticoids with acidosis is necessary for many of the physiological responses to acidosis: increased ammonium excretion, increased titratable acid, and increased proximal tubule sodium-hydrogen (Na+>/H+) exchange. In a pivotal study, Kinsella et al7Kinsella J Cujdik T Sacktor B Na+/H+ exchange activity in renal brush border membrane vesicles in response to metabolic acidosis: The role of glucocorticoids.Proc Natl Acad Sci U S A. 1984; 81: 630-634Crossref PubMed Scopus (86) Google Scholar showed that adrenalectomized animals failed to respond appropriately to metabolic acid loads in terms of ammonium and phosphate excretion; furthermore, this failure could be corrected by the administration of the synthetic glucocorticoid dexamethasone, without replacement of mineralocorticoids.7Kinsella J Cujdik T Sacktor B Na+/H+ exchange activity in renal brush border membrane vesicles in response to metabolic acidosis: The role of glucocorticoids.Proc Natl Acad Sci U S A. 1984; 81: 630-634Crossref PubMed Scopus (86) Google Scholar Parallel findings were made for Na+/H+ exchange in brush-border membrane vesicles: increased exchange with vesicles from acidotic animals with intact adrenals, no adaptation with vesicles from adrenalectomized animals even with acidosis, and restoration of the response to acidosis with dexamethasone treatment.7Kinsella J Cujdik T Sacktor B Na+/H+ exchange activity in renal brush border membrane vesicles in response to metabolic acidosis: The role of glucocorticoids.Proc Natl Acad Sci U S A. 1984; 81: 630-634Crossref PubMed Scopus (86) Google Scholar The cellular and molecular mechanisms of the NHE findings have now been characterized by Ambühl et al,1Ambühl P Yang X Peng Y Preisig P Moe O Alpern R Glucocorticoids enhance acid activation of the Na+/H+ exchanger 3 (NHE3).J Clin Invest. 1999; 103: 429-435Crossref PubMed Scopus (45) Google Scholar as discussed next. Of note, Na+/H+ exchange and phosphate excretion in the studies of Kinsella et al7Kinsella J Cujdik T Sacktor B Na+/H+ exchange activity in renal brush border membrane vesicles in response to metabolic acidosis: The role of glucocorticoids.Proc Natl Acad Sci U S A. 1984; 81: 630-634Crossref PubMed Scopus (86) Google Scholar increased just as much with dexamethasone in nonacidotic as in acidotic animals (or their membrane vesicles). Kinsella et al7Kinsella J Cujdik T Sacktor B Na+/H+ exchange activity in renal brush border membrane vesicles in response to metabolic acidosis: The role of glucocorticoids.Proc Natl Acad Sci U S A. 1984; 81: 630-634Crossref PubMed Scopus (86) Google Scholar proposed that glucocorticoids orchestrate the proximal tubule response to acidosis.The changes in ammonium excretion and Na+/H+ exchange previously discussed may be linked, at least in part. Ammonium is produced predominantly in the proximal tubule from glutamine and is secreted into the lumen probably by two mechanisms: (1) Na+-NH4+ exchange on the NHE, and (2) NH3 diffusion with trapping of NH4+ as the lumen pH decreases with Na+/H+ exchange and sodium-independent acidification through H+-adenosine triphosphatase.8Hamm L Simon E Ammonia transport in the proximal tubule.Miner Electrolyte Metab. 1990; 16: 283-290PubMed Google Scholar In other words, both mechanisms of ammonium secretion into the lumen depend on the apical membrane NHE. However, there are also other reasons that ammonium secretion is inadequate in the absence of glucocorticoids. Welbourne6Welbourne T Acidosis activation of the pituitary-adrenal-renal glutaminase I axis.Endocrinology. 1976; 99: 1071-1079Crossref PubMed Scopus (48) Google Scholar, 9Welbourne T Glucocorticoid control of ammoniagenesis in the proximal tubule.Semin Nephrol. 1990; 10: 339-349PubMed Google Scholar and others have shown that glucocorticoids enable acidosis to appropriately increase glutamine uptake, mitochondrial glutaminase, and total ammonium production.Increased glucocorticoids alone, without primary acidosis, increase endogenous acid production (EAP) and decrease proximal tubule phosphate reabsorption.10Hulter H Licht J Bonner E Glynn R Sebastian A Effects of glucocorticoid steroids on renal and systemic acid-base metabolism.Am J Physiol. 1980; 239: F30-F43PubMed Google Scholar, 11Hulter H Sigala J Sebastian A Effects of dexamethasone on renal and systemic acid-base metabolism.Kidney Int. 1981; 20: 43-49Crossref PubMed Scopus (19) Google Scholar, 12Anderson J Foster J The effect of cortisone on urinary phosphate excretion in man.Clin Sci. 1959; 18: 437-439PubMed Google Scholar, 13Freiberg J Kinsella J Sacktor B Glucocorticoids increase the Na+/H+ exchange and decrease the Na+ gradient-dependent phosphate-uptake systems in renal brush border membrane vesicles.Proc Natl Acad Sci U S A. 1982; 79: 4932-4936Crossref PubMed Scopus (121) Google Scholar The increased EAP may result from decreased protein synthesis and possibly from increased muscle catabolism, as discussed next. Urinary net acid excretion increases, partly in response to the increased EAP, but it eventually may exceed EAP, resulting in elevated plasma bicarbonate levels.10Hulter H Licht J Bonner E Glynn R Sebastian A Effects of glucocorticoid steroids on renal and systemic acid-base metabolism.Am J Physiol. 1980; 239: F30-F43PubMed Google Scholar, 11Hulter H Sigala J Sebastian A Effects of dexamethasone on renal and systemic acid-base metabolism.Kidney Int. 1981; 20: 43-49Crossref PubMed Scopus (19) Google Scholar The decreased phosphate reabsorption with glucocorticoids results from inhibition of the apical membrane sodium-dependent phosphate transporter13Freiberg J Kinsella J Sacktor B Glucocorticoids increase the Na+/H+ exchange and decrease the Na+ gradient-dependent phosphate-uptake systems in renal brush border membrane vesicles.Proc Natl Acad Sci U S A. 1982; 79: 4932-4936Crossref PubMed Scopus (121) Google Scholar; this will allow increased titratable acid excretion because phosphate is the main urinary buffer. More importantly quantitatively, ammonium excretion also increases.Another consequence of systemic acidosis also requires glucocorticoids: muscle breakdown. Although increased muscle catabolism in response to acidosis has been known for many years, recently, Mitch, Price, England, and their colleagues have shown a critical role of glucocorticoids in permitting the effects of acidosis (eg,14May R Kelly R Mitch W Metabolic acidosis stimulates protein degradation in rat muscle by a glucocorticoid-dependent mechanism.J Clin Invest. 1986; 77: 614-621Crossref PubMed Scopus (310) Google Scholar, 15Isozaki Y, Mitch W, England B, Price S: Protein degradation and increased mRNA encoding proteins of the ubiquitin-proteasome proteolytic pathway in BC3 H1 myocytes require an interaction between glucocorticoids and acidification. Proc Natl Acad Sci U S A 93:1967-1971,Google Scholar). In the degradative pathway of muscle proteins, the synergistic interactions of acidosis and glucocorticoids occur in regulating the messenger RNA (mRNA) levels of several key enzymes (eg,15Isozaki Y, Mitch W, England B, Price S: Protein degradation and increased mRNA encoding proteins of the ubiquitin-proteasome proteolytic pathway in BC3 H1 myocytes require an interaction between glucocorticoids and acidification. Proc Natl Acad Sci U S A 93:1967-1971,Google Scholar), a contrast with the results discussed below. Another potential site of interaction of acidosis with glucocorticoids is bone. In this case, there is no evidence that the effects of acidosis on bone are dependent on glucocorticoids or vice versa. However, both systemic acidosis and glucocorticoids cause increased bone resorption and increased urinary calcium; therefore, the combined effect is likely to be at least additive.In the article under discussion, Ambühl et al1Ambühl P Yang X Peng Y Preisig P Moe O Alpern R Glucocorticoids enhance acid activation of the Na+/H+ exchanger 3 (NHE3).J Clin Invest. 1999; 103: 429-435Crossref PubMed Scopus (45) Google Scholar used Opossum Kidney, Pelone (OKP) cells to address the mechanisms of the interaction of glucocorticoids with acidosis to stimulate proximal tubule Na+/H+ exchange. OKP cells are an opossum proximal tubule cell line that expresses apical membrane NHE3 as in the intact proximal tubule. NHE3 has now been well established as the chief isoform of Na+/H+ exchangers responsible for most of proximal tubule HCO3 reabsorption. The OKP cell line has been particularly useful to study a variety of proximal tubule transport processes. Ambühl et al1Ambühl P Yang X Peng Y Preisig P Moe O Alpern R Glucocorticoids enhance acid activation of the Na+/H+ exchanger 3 (NHE3).J Clin Invest. 1999; 103: 429-435Crossref PubMed Scopus (45) Google Scholar used a variety of functional and biochemical techniques in fairly standard methods. In these cells, they found that either in vitro acidosis (pH 6.8 versus 7.4) or in vitro hydrocortisone (HC; 10–7 to 10–8 mol/L) increased Na+/H+ exchange, as measured by recovery of intracellular pH from an acid load. The combination was additive (or perhaps more). However, a dose of HC (10–9) that had no independent effect also augmented the effect of the acid media. Control experiments showed that neither aldosterone nor an inhibitor of NHE1 had an effect on Na+/H+ exchange.Further experiments by Ambühl et al1Ambühl P Yang X Peng Y Preisig P Moe O Alpern R Glucocorticoids enhance acid activation of the Na+/H+ exchanger 3 (NHE3).J Clin Invest. 1999; 103: 429-435Crossref PubMed Scopus (45) Google Scholar addressed the molecular mechanisms of these functional effects. Both acidosis and glucocorticoids have been previously shown to increase NHE3 mRNA and protein levels. In the present studies, 10–9 mol/L of HC with normal pH media increased both mRNA and protein abundance of NHE3, despite the lack of functional effects in the absence of acidosis. Somewhat surprisingly, this low concentration of HC had additive or synergistic activity with acidosis on NHE3 protein synthesis, but not on mRNA levels. Importantly, Ambühl et al1Ambühl P Yang X Peng Y Preisig P Moe O Alpern R Glucocorticoids enhance acid activation of the Na+/H+ exchanger 3 (NHE3).J Clin Invest. 1999; 103: 429-435Crossref PubMed Scopus (45) Google Scholar additionally showed that 10–9 mol/L of HC enabled acidosis to increase Na+/H+ exchange in the absence of new protein synthesis (cycloheximide present), a posttranslational effect. At least part of this posttranslational effect appeared to be redistribution of NHE3 protein to the apical membrane (determined by biotinylation of apical membrane proteins).The studies by Ambühl et al1Ambühl P Yang X Peng Y Preisig P Moe O Alpern R Glucocorticoids enhance acid activation of the Na+/H+ exchanger 3 (NHE3).J Clin Invest. 1999; 103: 429-435Crossref PubMed Scopus (45) Google Scholar were obviously carefully and thoughtfully performed, and the results are important in providing new molecular mechanisms of the interaction of glucocorticoids and acidosis. However, as with any report, it is important to ask not only what is new or important, but also, what is wrong. Most articles, even in the most prestigious journals, have some potential flaws, residual uncertainties, or unanswered questions. For instance, the variability of baseline Na+/H+ exchange from experiment to experiment (compare Figs 2 and 51Ambühl P Yang X Peng Y Preisig P Moe O Alpern R Glucocorticoids enhance acid activation of the Na+/H+ exchanger 3 (NHE3).J Clin Invest. 1999; 103: 429-435Crossref PubMed Scopus (45) Google Scholar) provides one note of caution; unfortunately, this is problematic in many cultured cell systems. Some relatively minor additional details would have helped further define the relationship between acidosis and glucocorticoids. Does HC at higher concentrations have effects on antiporter activity in the absence of protein synthesis? Does HC alone without acidosis or acidosis alone without HC increase apical membrane NHE3 abundance? Why do acidosis and glucocorticoids not have at least additive effects on NHE3 mRNA levels? Despite these minor issues, the studies appear solid and extensive.As with any important new findings, a variety of new directions are also provided. For instance, what is the mechanism of increased insertion into the apical membrane? Because the activities of the apical NHE and the basolateral sodium bicarbonate transporter frequently change in parallel do glucocorticoids have similar effects on the basolateral sodium bicarbonate transporter? Are there similar multiple levels of interactions between acidosis and glucocorticoids in other physiological responses (eg, ammonia excretion)? Important regulatory processes for NHE3 have recently been shown (direct phosphorylation and interaction with regulatory proteins); are these mechanisms operative in the synergism of acidosis and glucocorticoids? Are other paracrine hormone systems activated? To some degree, the new questions raised by this study illustrate its importance.From a clinical perspective, the present study emphasizes the necessity for glucocorticoids in the normal response to acidosis; glucocorticoid-deficient patients will be unable to appropriately respond to or correct metabolic acidosis or acid loads. The interactions of glucocorticoids and acidosis occur not only in the kidney, but also in muscle and bone, in complex mechanisms. In understanding acid-base homeostasis and derangements of such, both mineralocorticoids and glucocorticoids are important considerations. The article by Ambühl et al1Ambühl P Yang X Peng Y Preisig P Moe O Alpern R Glucocorticoids enhance acid activation of the Na+/H+ exchanger 3 (NHE3).J Clin Invest. 1999; 103: 429-435Crossref PubMed Scopus (45) Google Scholar contributes valuable new information to this understanding. This month's discussion . . .The Journal Club focuses on an article entitled “Glucocorticoids Enhance Acid Activation of the Na+/H+ Exchanger 3 (NHE3)” (J Clin Invest 103: 429-435, 1999) by Patrice M. Ambühl, Xiaojing Yang, Yan Peng, Patricia A. Preisig, Orson W. Moe, and Robert J. Alpern. This month's discussion . . .The Journal Club focuses on an article entitled “Glucocorticoids Enhance Acid Activation of the Na+/H+ Exchanger 3 (NHE3)” (J Clin Invest 103: 429-435, 1999) by Patrice M. Ambühl, Xiaojing Yang, Yan Peng, Patricia A. Preisig, Orson W. Moe, and Robert J. Alpern. This month's discussion . . . The Journal Club focuses on an article entitled “Glucocorticoids Enhance Acid Activation of the Na+/H+ Exchanger 3 (NHE3)” (J Clin Invest 103: 429-435, 1999) by Patrice M. Ambühl, Xiaojing Yang, Yan Peng, Patricia A. Preisig, Orson W. Moe, and Robert J. Alpern. Glucocorticoids have an important role in the physiological response to systemic acidosis. This role is not only important from a physiological perspective, but also has important clinical implications. However, this interaction of glucocorticoids with acidosis has not been fully appreciated, except by a few groups. In the article under discussion, “Glucocorticoids Enhance Acid Activation of the Na+/H+ Exchanger 3 (NHE3),” Ambühl et al1Ambühl P Yang X Peng Y Preisig P Moe O Alpern R Glucocorticoids enhance acid activation of the Na+/H+ exchanger 3 (NHE3).J Clin Invest. 1999; 103: 429-435Crossref PubMed Scopus (45) Google Scholar explored the molecular mechanisms of this interaction in the proximal tubule. Adrenal insufficiency is often accompanied by metabolic acidosis, a result of decreased excretion of titratable acid and ammonium.2Sartorius O Calhoon D Pitts R Studies on the interrelationships of the adrenal cortex and renal ammonia excretion by the rat.Endocrinology. 1953; 52: 256-265Crossref PubMed Scopus (20) Google Scholar, 3Dubrovsky A Nair R Byers M Levine D Renal net acid excretion in the adrenalectomized rat.Kidney Int. 1981; 19: 516-528Crossref PubMed Scopus (32) Google Scholar Conversely, Cushing's syndrome frequently causes metabolic alkalosis. Although the effects of both these conditions have been attributed in part to distal tubule effects by mineralocorticoid receptors, glucocorticoids have important effects in the proximal tubule, particularly in response to acidosis. In adrenalectomized animals, glucocorticoids increase net acid excretion (ammonium plus titratable acid) more than aldosterone, despite a larger effect of the latter on reducing urine pH.4Wilcox C Cemerikic D Giebisch G Differential effects of acute mineralo- and glucocorticosteroid administration on renal acid elimination.Kidney Int. 1982; 21: 546-556Crossref PubMed Scopus (34) Google Scholar Importantly, in healthy animals or persons, metabolic acidosis results in a corticotropin-dependent increase in corticosteroids.2Sartorius O Calhoon D Pitts R Studies on the interrelationships of the adrenal cortex and renal ammonia excretion by the rat.Endocrinology. 1953; 52: 256-265Crossref PubMed Scopus (20) Google Scholar, 5Perez G Oster J Katz F Vaamonde C The effect of acute metabolic acidosis on plasma cortisol, renin activity and aldosterone.Hormone Res. 1979; 11: 12-21Crossref PubMed Scopus (40) Google Scholar, 6Welbourne T Acidosis activation of the pituitary-adrenal-renal glutaminase I axis.Endocrinology. 1976; 99: 1071-1079Crossref PubMed Scopus (48) Google Scholar In turn, the increase in glucocorticoids with acidosis is necessary for many of the physiological responses to acidosis: increased ammonium excretion, increased titratable acid, and increased proximal tubule sodium-hydrogen (Na+>/H+) exchange. In a pivotal study, Kinsella et al7Kinsella J Cujdik T Sacktor B Na+/H+ exchange activity in renal brush border membrane vesicles in response to metabolic acidosis: The role of glucocorticoids.Proc Natl Acad Sci U S A. 1984; 81: 630-634Crossref PubMed Scopus (86) Google Scholar showed that adrenalectomized animals failed to respond appropriately to metabolic acid loads in terms of ammonium and phosphate excretion; furthermore, this failure could be corrected by the administration of the synthetic glucocorticoid dexamethasone, without replacement of mineralocorticoids.7Kinsella J Cujdik T Sacktor B Na+/H+ exchange activity in renal brush border membrane vesicles in response to metabolic acidosis: The role of glucocorticoids.Proc Natl Acad Sci U S A. 1984; 81: 630-634Crossref PubMed Scopus (86) Google Scholar Parallel findings were made for Na+/H+ exchange in brush-border membrane vesicles: increased exchange with vesicles from acidotic animals with intact adrenals, no adaptation with vesicles from adrenalectomized animals even with acidosis, and restoration of the response to acidosis with dexamethasone treatment.7Kinsella J Cujdik T Sacktor B Na+/H+ exchange activity in renal brush border membrane vesicles in response to metabolic acidosis: The role of glucocorticoids.Proc Natl Acad Sci U S A. 1984; 81: 630-634Crossref PubMed Scopus (86) Google Scholar The cellular and molecular mechanisms of the NHE findings have now been characterized by Ambühl et al,1Ambühl P Yang X Peng Y Preisig P Moe O Alpern R Glucocorticoids enhance acid activation of the Na+/H+ exchanger 3 (NHE3).J Clin Invest. 1999; 103: 429-435Crossref PubMed Scopus (45) Google Scholar as discussed next. Of note, Na+/H+ exchange and phosphate excretion in the studies of Kinsella et al7Kinsella J Cujdik T Sacktor B Na+/H+ exchange activity in renal brush border membrane vesicles in response to metabolic acidosis: The role of glucocorticoids.Proc Natl Acad Sci U S A. 1984; 81: 630-634Crossref PubMed Scopus (86) Google Scholar increased just as much with dexamethasone in nonacidotic as in acidotic animals (or their membrane vesicles). Kinsella et al7Kinsella J Cujdik T Sacktor B Na+/H+ exchange activity in renal brush border membrane vesicles in response to metabolic acidosis: The role of glucocorticoids.Proc Natl Acad Sci U S A. 1984; 81: 630-634Crossref PubMed Scopus (86) Google Scholar proposed that glucocorticoids orchestrate the proximal tubule response to acidosis. The changes in ammonium excretion and Na+/H+ exchange previously discussed may be linked, at least in part. Ammonium is produced predominantly in the proximal tubule from glutamine and is secreted into the lumen probably by two mechanisms: (1) Na+-NH4+ exchange on the NHE, and (2) NH3 diffusion with trapping of NH4+ as the lumen pH decreases with Na+/H+ exchange and sodium-independent acidification through H+-adenosine triphosphatase.8Hamm L Simon E Ammonia transport in the proximal tubule.Miner Electrolyte Metab. 1990; 16: 283-290PubMed Google Scholar In other words, both mechanisms of ammonium secretion into the lumen depend on the apical membrane NHE. However, there are also other reasons that ammonium secretion is inadequate in the absence of glucocorticoids. Welbourne6Welbourne T Acidosis activation of the pituitary-adrenal-renal glutaminase I axis.Endocrinology. 1976; 99: 1071-1079Crossref PubMed Scopus (48) Google Scholar, 9Welbourne T Glucocorticoid control of ammoniagenesis in the proximal tubule.Semin Nephrol. 1990; 10: 339-349PubMed Google Scholar and others have shown that glucocorticoids enable acidosis to appropriately increase glutamine uptake, mitochondrial glutaminase, and total ammonium production. Increased glucocorticoids alone, without primary acidosis, increase endogenous acid production (EAP) and decrease proximal tubule phosphate reabsorption.10Hulter H Licht J Bonner E Glynn R Sebastian A Effects of glucocorticoid steroids on renal and systemic acid-base metabolism.Am J Physiol. 1980; 239: F30-F43PubMed Google Scholar, 11Hulter H Sigala J Sebastian A Effects of dexamethasone on renal and systemic acid-base metabolism.Kidney Int. 1981; 20: 43-49Crossref PubMed Scopus (19) Google Scholar, 12Anderson J Foster J The effect of cortisone on urinary phosphate excretion in man.Clin Sci. 1959; 18: 437-439PubMed Google Scholar, 13Freiberg J Kinsella J Sacktor B Glucocorticoids increase the Na+/H+ exchange and decrease the Na+ gradient-dependent phosphate-uptake systems in renal brush border membrane vesicles.Proc Natl Acad Sci U S A. 1982; 79: 4932-4936Crossref PubMed Scopus (121) Google Scholar The increased EAP may result from decreased protein synthesis and possibly from increased muscle catabolism, as discussed next. Urinary net acid excretion increases, partly in response to the increased EAP, but it eventually may exceed EAP, resulting in elevated plasma bicarbonate levels.10Hulter H Licht J Bonner E Glynn R Sebastian A Effects of glucocorticoid steroids on renal and systemic acid-base metabolism.Am J Physiol. 1980; 239: F30-F43PubMed Google Scholar, 11Hulter H Sigala J Sebastian A Effects of dexamethasone on renal and systemic acid-base metabolism.Kidney Int. 1981; 20: 43-49Crossref PubMed Scopus (19) Google Scholar The decreased phosphate reabsorption with glucocorticoids results from inhibition of the apical membrane sodium-dependent phosphate transporter13Freiberg J Kinsella J Sacktor B Glucocorticoids increase the Na+/H+ exchange and decrease the Na+ gradient-dependent phosphate-uptake systems in renal brush border membrane vesicles.Proc Natl Acad Sci U S A. 1982; 79: 4932-4936Crossref PubMed Scopus (121) Google Scholar; this will allow increased titratable acid excretion because phosphate is the main urinary buffer. More importantly quantitatively, ammonium excretion also increases. Another consequence of systemic acidosis also requires glucocorticoids: muscle breakdown. Although increased muscle catabolism in response to acidosis has been known for many years, recently, Mitch, Price, England, and their colleagues have shown a critical role of glucocorticoids in permitting the effects of acidosis (eg,14May R Kelly R Mitch W Metabolic acidosis stimulates protein degradation in rat muscle by a glucocorticoid-dependent mechanism.J Clin Invest. 1986; 77: 614-621Crossref PubMed Scopus (310) Google Scholar, 15Isozaki Y, Mitch W, England B, Price S: Protein degradation and increased mRNA encoding proteins of the ubiquitin-proteasome proteolytic pathway in BC3 H1 myocytes require an interaction between glucocorticoids and acidification. Proc Natl Acad Sci U S A 93:1967-1971,Google Scholar). In the degradative pathway of muscle proteins, the synergistic interactions of acidosis and glucocorticoids occur in regulating the messenger RNA (mRNA) levels of several key enzymes (eg,15Isozaki Y, Mitch W, England B, Price S: Protein degradation and increased mRNA encoding proteins of the ubiquitin-proteasome proteolytic pathway in BC3 H1 myocytes require an interaction between glucocorticoids and acidification. Proc Natl Acad Sci U S A 93:1967-1971,Google Scholar), a contrast with the results discussed below. Another potential site of interaction of acidosis with glucocorticoids is bone. In this case, there is no evidence that the effects of acidosis on bone are dependent on glucocorticoids or vice versa. However, both systemic acidosis and glucocorticoids cause increased bone resorption and increased urinary calcium; therefore, the combined effect is likely to be at least additive. In the article under discussion, Ambühl et al1Ambühl P Yang X Peng Y Preisig P Moe O Alpern R Glucocorticoids enhance acid activation of the Na+/H+ exchanger 3 (NHE3).J Clin Invest. 1999; 103: 429-435Crossref PubMed Scopus (45) Google Scholar used Opossum Kidney, Pelone (OKP) cells to address the mechanisms of the interaction of glucocorticoids with acidosis to stimulate proximal tubule Na+/H+ exchange. OKP cells are an opossum proximal tubule cell line that expresses apical membrane NHE3 as in the intact proximal tubule. NHE3 has now been well established as the chief isoform of Na+/H+ exchangers responsible for most of proximal tubule HCO3 reabsorption. The OKP cell line has been particularly useful to study a variety of proximal tubule transport processes. Ambühl et al1Ambühl P Yang X Peng Y Preisig P Moe O Alpern R Glucocorticoids enhance acid activation of the Na+/H+ exchanger 3 (NHE3).J Clin Invest. 1999; 103: 429-435Crossref PubMed Scopus (45) Google Scholar used a variety of functional and biochemical techniques in fairly standard methods. In these cells, they found that either in vitro acidosis (pH 6.8 versus 7.4) or in vitro hydrocortisone (HC; 10–7 to 10–8 mol/L) increased Na+/H+ exchange, as measured by recovery of intracellular pH from an acid load. The combination was additive (or perhaps more). However, a dose of HC (10–9) that had no independent effect also augmented the effect of the acid media. Control experiments showed that neither aldosterone nor an inhibitor of NHE1 had an effect on Na+/H+ exchange. Further experiments by Ambühl et al1Ambühl P Yang X Peng Y Preisig P Moe O Alpern R Glucocorticoids enhance acid activation of the Na+/H+ exchanger 3 (NHE3).J Clin Invest. 1999; 103: 429-435Crossref PubMed Scopus (45) Google Scholar addressed the molecular mechanisms of these functional effects. Both acidosis and glucocorticoids have been previously shown to increase NHE3 mRNA and protein levels. In the present studies, 10–9 mol/L of HC with normal pH media increased both mRNA and protein abundance of NHE3, despite the lack of functional effects in the absence of acidosis. Somewhat surprisingly, this low concentration of HC had additive or synergistic activity with acidosis on NHE3 protein synthesis, but not on mRNA levels. Importantly, Ambühl et al1Ambühl P Yang X Peng Y Preisig P Moe O Alpern R Glucocorticoids enhance acid activation of the Na+/H+ exchanger 3 (NHE3).J Clin Invest. 1999; 103: 429-435Crossref PubMed Scopus (45) Google Scholar additionally showed that 10–9 mol/L of HC enabled acidosis to increase Na+/H+ exchange in the absence of new protein synthesis (cycloheximide present), a posttranslational effect. At least part of this posttranslational effect appeared to be redistribution of NHE3 protein to the apical membrane (determined by biotinylation of apical membrane proteins). The studies by Ambühl et al1Ambühl P Yang X Peng Y Preisig P Moe O Alpern R Glucocorticoids enhance acid activation of the Na+/H+ exchanger 3 (NHE3).J Clin Invest. 1999; 103: 429-435Crossref PubMed Scopus (45) Google Scholar were obviously carefully and thoughtfully performed, and the results are important in providing new molecular mechanisms of the interaction of glucocorticoids and acidosis. However, as with any report, it is important to ask not only what is new or important, but also, what is wrong. Most articles, even in the most prestigious journals, have some potential flaws, residual uncertainties, or unanswered questions. For instance, the variability of baseline Na+/H+ exchange from experiment to experiment (compare Figs 2 and 51Ambühl P Yang X Peng Y Preisig P Moe O Alpern R Glucocorticoids enhance acid activation of the Na+/H+ exchanger 3 (NHE3).J Clin Invest. 1999; 103: 429-435Crossref PubMed Scopus (45) Google Scholar) provides one note of caution; unfortunately, this is problematic in many cultured cell systems. Some relatively minor additional details would have helped further define the relationship between acidosis and glucocorticoids. Does HC at higher concentrations have effects on antiporter activity in the absence of protein synthesis? Does HC alone without acidosis or acidosis alone without HC increase apical membrane NHE3 abundance? Why do acidosis and glucocorticoids not have at least additive effects on NHE3 mRNA levels? Despite these minor issues, the studies appear solid and extensive. As with any important new findings, a variety of new directions are also provided. For instance, what is the mechanism of increased insertion into the apical membrane? Because the activities of the apical NHE and the basolateral sodium bicarbonate transporter frequently change in parallel do glucocorticoids have similar effects on the basolateral sodium bicarbonate transporter? Are there similar multiple levels of interactions between acidosis and glucocorticoids in other physiological responses (eg, ammonia excretion)? Important regulatory processes for NHE3 have recently been shown (direct phosphorylation and interaction with regulatory proteins); are these mechanisms operative in the synergism of acidosis and glucocorticoids? Are other paracrine hormone systems activated? To some degree, the new questions raised by this study illustrate its importance. From a clinical perspective, the present study emphasizes the necessity for glucocorticoids in the normal response to acidosis; glucocorticoid-deficient patients will be unable to appropriately respond to or correct metabolic acidosis or acid loads. The interactions of glucocorticoids and acidosis occur not only in the kidney, but also in muscle and bone, in complex mechanisms. In understanding acid-base homeostasis and derangements of such, both mineralocorticoids and glucocorticoids are important considerations. The article by Ambühl et al1Ambühl P Yang X Peng Y Preisig P Moe O Alpern R Glucocorticoids enhance acid activation of the Na+/H+ exchanger 3 (NHE3).J Clin Invest. 1999; 103: 429-435Crossref PubMed Scopus (45) Google Scholar contributes valuable new information to this understanding." @default.
• W2149162172 created "2016-06-24" @default.
• W2149162172 creator A5085254796 @default.
• W2149162172 date "1999-11-01" @default.
• W2149162172 modified "2023-09-24" @default.
• W2149162172 title "Role of glucocorticoids in acidosis" @default.
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