Pendrin in the mouse kidney is primarily regulated by Cl− excretion but also by systemic metabolic acidosis

2008 ◽  
Vol 295 (6) ◽  
pp. C1658-C1667 ◽  
Author(s):  
Patricia Hafner ◽  
Rosa Grimaldi ◽  
Paola Capuano ◽  
Giovambattista Capasso ◽  
Carsten A. Wagner
Keyword(s):  
Metabolic Acidosis ◽  
Collecting Duct ◽  
Relative Number ◽  
High Protein ◽  
Acid Excretion ◽  
Acid Base ◽  
Urinary Acidification ◽  
Apical Side ◽  
Acid Base Status ◽  
Net Acid Excretion

The Cl−/anion exchanger pendrin (SLC26A4) is expressed on the apical side of renal non-type A intercalated cells. The abundance of pendrin is reduced during metabolic acidosis induced by oral NH4Cl loading. More recently, it has been shown that pendrin expression is increased during conditions associated with decreased urinary Cl− excretion and decreased upon Cl− loading. Hence, it is unclear if pendrin regulation during NH4Cl-induced acidosis is primarily due the Cl− load or acidosis. Therefore, we treated mice to increase urinary acidification, induce metabolic acidosis, or provide an oral Cl− load and examined the systemic acid-base status, urinary acidification, urinary Cl− excretion, and pendrin abundance in the kidney. NaCl or NH4Cl increased urinary Cl− excretion, whereas (NH4)2SO4, Na2SO4, and acetazolamide treatments decreased urinary Cl− excretion. NH4Cl, (NH4)2SO4, and acetazolamide caused metabolic acidosis and stimulated urinary net acid excretion. Pendrin expression was reduced under NaCl, NH4Cl, and (NH4)2SO4 loading and increased with the other treatments. (NH4)2SO4 and acetazolamide treatments reduced the relative number of pendrin-expressing cells in the collecting duct. In a second series, animals were kept for 1 and 2 wk on a low-protein (20%) diet or a high-protein (50%) diet. The high-protein diet slightly increased urinary Cl− excretion and strongly stimulated net acid excretion but did not alter pendrin expression. Thus, pendrin expression is primarily correlated with urinary Cl− excretion but not blood Cl−. However, metabolic acidosis caused by acetazolamide or (NH4)2SO4 loading prevented the increase or even reduced pendrin expression despite low urinary Cl− excretion, suggesting an independent regulation by acid-base status.

Inner medullary collecting duct function during rebound alkalemia

1987 ◽  
Vol 252 (4) ◽  
pp. F712-F716
Author(s):  
H. H. Bengele ◽  
E. R. McNamara ◽  
J. H. Schwartz ◽  
E. A. Alexander
Keyword(s):  
Collecting Duct ◽  
Acid Excretion ◽  
Acid Base ◽  
Proton Secretion ◽  
Inner Medullary Collecting Duct ◽  
Titratable Acid ◽  
Base Parameters ◽  
Arterial Ph ◽  
Medullary Collecting Duct ◽  
Net Acid Excretion

Rats, made acidemic when fed NH4Cl, become alkalemic with discontinuation of the NH4Cl. This phenomenon has been called rebound metabolic alkalemia (RMA). This study examines the function of the inner medullary collecting duct (IMCD) during RMA. Rats drank only 1.5% NH4Cl for 5 days and then water for 16 h prior to study, yielding an arterial pH = 7.50 +/- 0.01, PCO2 = 39 +/- 1 mmHg, and bicarbonate = 29.5 +/- 1.0 mM. The IMCD data were obtained by microcatheterization from deep (1.5-3.0 mm) and tip (0.2-0.5 mm) samples. Equilibrium pH decreased from 5.92 +/- 0.09 (n = 20) to 5.38 +/- 0.04 (n = 20) and PCO2 increased from 32 +/- 1 to 38 +/- 1 mmHg between deep and tip samples. Bicarbonate delivery decreased from 37 +/- 8 to 7 +/- 1 nmol/min. Titratable acid and ammonium delivery increased from 284 +/- 52 to 347 +/- 62 nmol/min and from 549 +/- 38 to 685 +/- 40 nmol/min, respectively. Calculated net acid excretion increased from 796 +/- 88 to 1,026 +/- 95 nmol/min. Thus during RMA, proton secretion continues along the IMCD, although there is a systemic alkalemia. It appears that factors in addition to systemic acid-base parameters are important in the regulation of proton secretion by the IMCD.

scholarly journals Effect of growth hormone on renal and systemic acid-base homeostasis in humans

1998 ◽  
Vol 274 (4) ◽  
pp. F650-F657 ◽  
Author(s):  
Anita Sicuro ◽  
Katia Mahlbacher ◽  
Henry N. Hulter ◽  
Reto Krapf
Keyword(s):  
Growth Hormone ◽  
Metabolic Acidosis ◽  
Recombinant Human Growth Hormone ◽  
Human Growth ◽  
Normal Subjects ◽  
Acid Excretion ◽  
Bicarbonate Concentration ◽  
Acid Base ◽  
Plasma Bicarbonate ◽  
Net Acid Excretion

The effects of recombinant human growth hormone (GH, 0.1 U ⋅ kg body wt−1 ⋅ 12 h−1) on systemic and renal acid-base homeostasis were investigated in six normal subjects with preexisting sustained chronic metabolic acidosis, induced by NH4Cl administration (4.2 mmol ⋅ kg body wt−1 ⋅ day−1). GH administration increased and maintained plasma bicarbonate concentration from 14.1 ± 1.4 to 18.6 ± 1.1 mmol/l ( P < 0.001). The GH-induced increase in plasma bicarbonate concentration was the consequence of a significant increase in net acid excretion that was accounted for largely by an increase in renal [Formula: see text]excretion sufficient in magnitude to override a decrease in urinary titratable acid excretion. During GH administration, urinary pH increased and correlated directly and significantly with urinary[Formula: see text] concentration. Urinary net acid excretion rates were not different during the steady-state periods of acidosis and acidosis with GH administration. Glucocorticoid and mineralocorticoid activities increased significantly in response to acidosis and were suppressed (glucocorticoid) or decreased to control levels (mineralocorticoid) by GH. The partial correction of metabolic acidosis occurred despite GH-induced renal sodium retention (180 mmol; gain in weight of 1.8 ± 0.2 kg, P< 0.005) and decreased glucocorticoid and mineralocorticoid activities. Thus GH (and/or insulin-like growth factor I) increased plasma bicarbonate concentration and partially corrected metabolic acidosis. This effect was generated in large part by and maintained fully by a renal mechanism (i.e., increased renal NH3 production and[Formula: see text]/net acid excretion).

Ureter obstruction alters expression of renal acid-base transport proteins in rat kidney

2008 ◽  
Vol 295 (2) ◽  
pp. F497-F506 ◽  
Author(s):  
Guixian Wang ◽  
Chunling Li ◽  
Soo Wan Kim ◽  
Troels Ring ◽  
Jianguo Wen ◽  
...  
Keyword(s):  
Metabolic Acidosis ◽  
Molecular Mechanisms ◽  
Urinary Tract Obstruction ◽  
Collecting Duct ◽  
Rat Kidney ◽  
Acid Base ◽  
Ureter Obstruction ◽  
Urinary Acidification ◽  
Medullary Collecting Duct ◽  
Type 3

Urinary tract obstruction impairs renal function and is often associated with a urinary acidification defect caused by diminished net H+ secretion and/or HCO3− reabsorption. To identify the molecular mechanisms of these defects, protein expression of key acid-base transporters were examined along the renal nephron and collecting duct of kidneys from rats subjected to 24-h bilateral ureteral obstruction (BUO), 4 days after release of BUO (BUO-R), or BUO-R rats with experimentally induced metabolic acidosis (BUO-A). Semiquantitative immunoblotting revealed that BUO caused a significant reduction in the expression of the type 3 Na+/H+ exchanger (NHE3) in the cortex (21 ± 4%), electrogenic Na+/HCO3− cotransporter (NBC1; 71 ± 5%), type 1 bumetanide-sensitive Na+-K+-2Cl− cotransporter (NKCC2; 3 ± 1%), electroneutral Na+/HCO3− cotransporter (NBCn1; 46 ± 7%), and anion exchanger (pendrin; 87 ± 2%). The expression of H+-ATPase increased in the inner medullary collecting duct (152 ± 13%). These changes were confirmed by immunocytochemistry. In BUO-R rats, there was a persistent downregulation of all the acid-base transporters including H+-ATPase. Two days of NH4Cl loading reduced plasma pH and HCO3− levels in BUO-A rats. The results demonstrate that the expression of multiple renal acid-base transporters are markedly altered in response to BUO, which may be responsible for development of metabolic acidosis and contribute to the urinary acidification defect after release of the obstruction.

NBCn1 Increases NH4+ Reabsorption Across Thick Ascending Limbs, the Capacity for Urinary NH4+ Excretion, and Early Recovery from Metabolic Acidosis

2021 ◽  
pp. ASN.2019060613
Author(s):  
Jeppe S. M. Olsen ◽  
Samuel Svendsen ◽  
Peder Berg ◽  
Vibeke S. Dam ◽  
Mads V. Sorensen ◽  
...  
Keyword(s):  
Metabolic Acidosis ◽  
Knockout Mice ◽  
Acid Excretion ◽  
Wild Type ◽  
Acid Base ◽  
Early Recovery ◽  
Spot Urine ◽  
Arterial Blood ◽  
Blood Ph ◽  
Net Acid Excretion

BackgroundThe electroneutral Na+/HCO3− cotransporter NBCn1 (Slc4a7) is expressed in basolateral membranes of renal medullary thick ascending limbs (mTALs). However, direct evidence that NBCn1 contributes to acid-base handling in mTALs, urinary net acid excretion, and systemic acid-base homeostasis has been lacking.MethodsMetabolic acidosis was induced in wild-type and NBCn1 knockout mice. Fluorescence-based intracellular pH recordings were performed and NH4+ transport measured in isolated perfused mTALs. Quantitative RT-PCR and immunoblotting were used to evaluate NBCn1 expression. Tissue [NH4+] was measured in renal biopsies, NH4+ excretion and titratable acid quantified in spot urine, and arterial blood gasses evaluated in normoventilated mice.ResultsBasolateral Na+/HCO3− cotransport activity was similar in isolated perfused mTALs from wild-type and NBCn1 knockout mice under control conditions. During metabolic acidosis, basolateral Na+/HCO3− cotransport activity increased four-fold in mTALs from wild-type mice, but remained unchanged in mTALs from NBCn1 knockout mice. Correspondingly, NBCn1 protein expression in wild-type mice increased ten-fold in the inner stripe of renal outer medulla during metabolic acidosis. During systemic acid loading, knockout of NBCn1 inhibited the net NH4+ reabsorption across mTALs by approximately 60%, abolished the renal corticomedullary NH4+ gradient, reduced the capacity for urinary NH4+ excretion by approximately 50%, and delayed recovery of arterial blood pH and standard [HCO3−] from their initial decline.ConclusionsDuring metabolic acidosis, NBCn1 is required for the upregulated basolateral HCO3− uptake and transepithelial NH4+ reabsorption in mTALs, renal medullary NH4+ accumulation, urinary NH4+ excretion, and early recovery of arterial blood pH and standard [HCO3−]. These findings support that NBCn1 facilitates urinary net acid excretion by neutralizing intracellular H+ released during NH4+ reabsorption across mTALs.

Renal and systemic acid-base effects of chronic spironolactone administration

1981 ◽  
Vol 240 (5) ◽  
pp. F381-F387
Author(s):  
H. N. Hulter ◽  
E. L. Bonner ◽  
R. D. Glynn ◽  
A. Sebastian
Keyword(s):  
Metabolic Acidosis ◽  
Chronic Administration ◽  
Nitrogen Excretion ◽  
Acid Excretion ◽  
Renal Secretion ◽  
Acid Base ◽  
Sulfuric Acid Production ◽  
Renal Tubular ◽  
Mineralocorticoid Activity ◽  
Net Acid Excretion

Studies in dogs were carried out to investigate the effects of chronic administration of the mineralcorticoid antagonist spironolactone (15 mg/kg orally) on renal and systemic acid-base metabolism. In adrenalectomized dogs administered fixed mineralocorticoid and glucocorticoid replacement, spironolactone resulted in a definite renal antimineralocorticoid effect, as evidenced by natriuresis and chloruresis, and sustained metabolic acidosis and hyperkalemia due in part to impaired renal secretion of hydrogen and potassium. In adrenalectomized dogs receiving physiological glucocorticoid without mineralocorticoid, metabolic acidosis also occurred, but a marked stimulatory effect of spironolactone on net acid excretion occurred in association with increased urinary SO4-2 and total nitrogen excretion. Accordingly, spironolactone results in sustained renal tubular acidosis when administered in the presence of constant physiological levels of mineralocorticoid and glucocorticoid steroids. When administered under conditions of complete lack of mineralocorticoid activity, spironolactone exerts systemic and renal acid-base effects similar to those of a glucocorticoid steroid, namely, increased protein catabolism and sulfuric acid production with resultant extrarenal metabolic acidosis associated with increased net acid excretion.

Inherited Proximal and Distal Renal Tubular Acidosis

2017 ◽  
Author(s):  
Patricia Valles ◽  
Jesus Moran-Farias ◽  
Daniel Batlle
Keyword(s):  
Metabolic Acidosis ◽  
Renal Tubular Acidosis ◽  
Distal Renal Tubular Acidosis ◽  
Anion Gap ◽  
Intercalated Cells ◽  
Acid Excretion ◽  
Acid Base ◽  
Urine Ph ◽  
Renal Tubular ◽  
Net Acid Excretion

Acid-base homeostasis by the kidney is maintained through proximal tubular reclamation of filtered bicarbonate and the excretion of the daily acid load by collecting duct type A intercalated cells. The impairment of either process results in renal tubular acidosis (RTA), a group of disorders characterized by a reduced net acid excretion and a persistent hyperchloremic, non–anion gap metabolic acidosis. The primary or hereditary forms of proximal (pRTA) and distal renal tubular acidosis (dRTA) have received increased attention because of advances in the understanding of the molecular mechanism, whereby mutations in the main proteins involved in acid-base transport result in either reduced bicarbonate reabsorption or reduced H+ secretion and impaired acid excretion. dRTA is characterized by reduced net acid excretion and an inability to lower urine pH despite severe acidemia (but minimal HCO3– wastage). pRTA (type 2), by contrast, is characterized by marked HCO3– wastage but preserved ability to lower urine pH when plasma HCO3– (and therefore filtered HCO3–) is below a certain threshold. In children with dRTA, growth retardation caused by chronic metabolic acidosis is the key manifestation but is fully reversible with appropriate alkali therapy if initiated early in life. A striking manifestation of many patients with dRTA is the development of severe hypokalemia that may cause muscle paralysis. In this review, we discuss these types of hereditary RTA and the mechanisms involved in the genesis of these inherited tubular disorders. This review contains 5 figures, 1 table, and 103 references. Key words: Proximal renal tubular acidosis (pRTA), Distal renal tubular acidosis (dRTA), Hyperchloremic, non–anion gap metabolic acidosis, Hypokalemia, Fractional HCO3– excretion, Urinary gap, Fanconi Syndrome.ATP6V1B1 and ATP6V0A4 gene mutations . Intercalated cells ,

scholarly journals Ca2+-driven intestinal HCO3− secretion and CaCO3 precipitation in the European flounder in vivo: influences on acid-base regulation and blood gas transport

2010 ◽  
Vol 298 (4) ◽  
pp. R870-R876 ◽  
Author(s):  
Christopher A. Cooper ◽  
Jonathan M. Whittamore ◽  
Rod W. Wilson
Keyword(s):  
Teleost Fish ◽  
Gas Transport ◽  
Driving Forces ◽  
Marine Teleost ◽  
Acid Excretion ◽  
Acid Base ◽  
Marine Teleost Fish ◽  
Net Acid Excretion

Marine teleost fish continuously ingest seawater to prevent dehydration and their intestines absorb fluid by mechanisms linked to three separate driving forces: 1) cotransport of NaCl from the gut fluid; 2) bicarbonate (HCO3−) secretion and Cl− absorption via Cl−/HCO3− exchange fueled by metabolic CO2; and 3) alkaline precipitation of Ca2+ as insoluble CaCO3, which aids H2O absorption). The latter two processes involve high rates of epithelial HCO3− secretion stimulated by intestinal Ca2+ and can drive a major portion of water absorption. At higher salinities and ambient Ca2+ concentrations the osmoregulatory role of intestinal HCO3− secretion is amplified, but this has repercussions for other physiological processes, in particular, respiratory gas transport (as it is fueled by metabolic CO2) and acid-base regulation (as intestinal cells must export H+ into the blood to balance apical HCO3− secretion). The flounder intestine was perfused in vivo with salines containing 10, 40, or 90 mM Ca2+. Increasing the luminal Ca2+ concentration caused a large elevation in intestinal HCO3− production and excretion. Additionally, blood pH decreased (−0.13 pH units) and plasma partial pressure of CO2 (Pco2) levels were elevated (+1.16 mmHg) at the highest Ca perfusate level after 3 days of perfusion. Increasing the perfusate [Ca2+] also produced proportional increases in net acid excretion via the gills. When the net intestinal flux of all ions across the intestine was calculated, there was a greater absorption of anions than cations. This missing cation flux was assumed to be protons, which vary with an almost 1:1 relationship with net acid excretion via the gill. This study illustrates the intimate link between intestinal HCO3− production and osmoregulation with acid-base balance and respiratory gas exchange and the specific controlling role of ingested Ca2+ independent of any other ion or overall osmolality in marine teleost fish.

Role of organic anions in renal response to dietary acid and base loads

1989 ◽  
Vol 257 (2) ◽  
pp. F170-F176 ◽  
Author(s):  
J. C. Brown ◽  
R. K. Packer ◽  
M. A. Knepper
Keyword(s):  
Organic Anion ◽  
Organic Anions ◽  
Acid Excretion ◽  
Acid Base Balance ◽  
Acid Base ◽  
Urine Ph ◽  
Renal Response ◽  
Base Balance ◽  
Net Acid Excretion

Bicarbonate is formed when organic anions are oxidized systemically. Therefore, changes in organic anion excretion can affect systemic acid-base balance. To assess the role of organic anions in urinary acid-base excretion, we measured urinary excretion in control rats, NaHCO3-loaded rats, and NH4Cl-loaded rats. Total organic anions were measured by the titration method of Van Slyke. As expected, NaHCO3 loading increased urine pH and decreased net acid excretion (NH4+ + titratable acid - HCO3-), whereas NH4Cl loading had the opposite effect. Organic anion excretion was increased in response to NaHCO3 loading and decreased in response to NH4Cl loading. We quantified the overall effect of organic ion plus inorganic buffer ion excretion on acid-base balance. The amounts of organic anions excreted by all animals in this study were greater than the amounts of NH4+, HCO3-, or titratable acidity excreted. In addition, in response to acid and alkali loading, changes in urinary organic anion excretion were 40-50% as large as changes in net acid excretion. We conclude that, in rats, regulation of organic anion excretion can contribute importantly to the overall renal response to acid-base disturbances.

Studies on the Pathophysiology of Encephalopathy in Reye's Syndrome: Hyperammonemia in Reye's Syndrome

PEDIATRICS ◽  
1975 ◽  
Vol 56 (6) ◽  
pp. 999-1004
Author(s):  
Daniel C. Shannon ◽  
Robert De Long ◽  
Barry Bercu ◽  
Thomas Glick ◽  
John T. Herrin ◽  
...  
Keyword(s):  
Metabolic Acidosis ◽  
Venous Drainage ◽  
Respiratory Alkalosis ◽  
Ammonia Concentration ◽  
Reye's Syndrome ◽  
Acid Base ◽  
Arterial Blood ◽  
Cerebral Venous Drainage ◽  
Acid Base Status ◽  
The Brain

The initial acid-base status of eight survivors of Reye's syndrome was characterized by acute respiratory alkalosis (Pco2=32 mm Hg; Hco3-= 22.0 mEq/liter) while that of eight children who died was associated with metabolic acidosis as well (HCO3-=10.0 mEq/liter). Arterialinternal jugular venous ammonia concentration differences on day 1 (299 mg/100 ml) and day 2 (90 mg/ 100 ml) reflected cerebral uptake of ammonia while those on days 3 and 4 (-43 and -55 mg/100 ml) demonstrated cerebral release. Arterial blood hyperammonemia can be detoxified safely in the brain as long as the levels do not exceed approximately 300µg/100 ml. Beyond that level lactic acidosis is observed, particularly in cerebral venous drainage. Arterial blood hyperammonemia was also related to the extent of alveolar hyperventilation. These findings are very similar to those seen in experimental hyperammonemia and support the concept that neurotoxicity in children with Reye's syndrome is at least partly due to impaired oxidative metabolism secondary to hyperammonemia.

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