scholarly journals Carbonic anhydrase 2 deficiency leads to increased pyelonephritis susceptibility

2014 ◽  
Vol 307 (7) ◽  
pp. F869-F880 ◽  
Author(s):  
David S. Hains ◽  
Xi Chen ◽  
Vijay Saxena ◽  
Evan Barr-Beare ◽  
Weisi Flemming ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Intercalated Cells ◽  
Bacterial Clearance ◽  
Wild Type ◽  
Acid Base ◽  
Wild Type Littermate ◽  
Innate Defense ◽  
Bacterial Response ◽  
Infection Susceptibility ◽  
Acid Base Status

Carbonic anhydrase 2 regulates acid-base homeostasis, and recent findings have indicated a correlation between cellular control of acid-base status and the innate defense of the kidney. Mice deficient in carbonic anhydrase 2 ( Car2−/− mice) have metabolic acidosis, impaired urine acidification, and are deficient in normal intercalated cells. The objective of the present study was to evaluate the biological consequences of carbonic anhydrase 2 deficiency in a murine model of pyelonephritis. Infection susceptibility and transcription of bacterial response components in Car2−/− mice were compared with wild-type littermate controls. Car2−/− mice had increased kidney bacterial burdens along with decreased renal bacterial clearance after inoculation compared with wild-type mice. Standardization of the urine pH and serum HCO3− levels did not substantially alter kidney infection susceptibility between wild-type and Car2−/− mice; thus, factors other than acid-base status are responsible. Car2−/− mice had significantly increased neutrophil-gelatinase-associated lipocalin mRNA and protein and expression at baseline and a marked decreased ability to upregulate key bacterial response genes during pyelonephritis. Our findings provide in vivo evidence that supports a role for carbonic anhydrase 2 and intercalated cells in promoting renal bacterial clearance. Decreased carbonic anhydrase expression results in increased antimicrobial peptide production by cells other than renal intercalated cells, which is not sufficient to prevent infection after a bacterial challenge.

Expression of rat kidney anion exchanger 1 in type A intercalated cells in metabolic acidosis and alkalosis

1999 ◽  
Vol 277 (6) ◽  
pp. F841-F849 ◽  
Author(s):  
Saskia Huber ◽  
Esther Asan ◽  
Thomas Jöns ◽  
Christiane Kerscher ◽  
Bernd Püschel ◽  
...  
Keyword(s):  
Anion Exchanger ◽  
Direct Evidence ◽  
Rat Kidney ◽  
Enzyme Reaction ◽  
Type A ◽  
Mrna Levels ◽  
Intercalated Cells ◽  
Acid Base ◽  
Anion Exchanger 1 ◽  
Acid Base Status

By enzyme-linked in situ hybridization (ISH), direct evidence is provided that acid-secreting intercalated cells (type A IC) of both the cortical and medullary collecting ducts of the rat kidney selectively express the mRNA of the kidney splice variant of anion exchanger 1 (kAE1) and no detectable levels of the erythrocyte AE1 (eAE1) mRNA. Using single-cell quantification by microphotometry of ISH enzyme reaction, medullary type A IC were found to contain twofold higher kAE1 mRNA levels compared with cortical type A IC. These differences correspond to the higher intensity of immunostaining in medullary versus cortical type A IC. Chronic changes of acid-base status induced by addition of NH4Cl (acidosis) or NaHCO3 (alkalosis) to the drinking water resulted in up to 35% changes of kAE1 mRNA levels in both cortical and medullary type A IC. These experiments provide direct evidence at the cellular level of kAE1 expression in type A IC and show moderate capacity of type A IC to respond to changes of acid-base status by modulation of kAE1 mRNA levels.

Cellular actions of cAMP on HCO3(-)-secreting cells of rabbit CCD: dependence on in vivo acid-base status

1994 ◽  
Vol 266 (4) ◽  
pp. F528-F535 ◽  
Author(s):  
C. Emmons ◽  
J. B. Stokes
Keyword(s):  
Anion Exchanger ◽  
Collecting Duct ◽  
Basolateral Membrane ◽  
Disulfonic Acid ◽  
Intercalated Cells ◽  
Cortical Collecting Duct ◽  
Acid Base ◽  
Acid Base Status

HCO3- secretion by cortical collecting duct (CCD) occurs via beta-intercalated cells. In vitro CCD HCO3- secretion is modulated by both the in vivo acid-base status of the animal and by adenosine 3',5'-cyclic monophosphate (cAMP). To investigate the mechanism of cAMP-induced HCO3- secretion, we measured intracellular pH (pHi) of individual beta-intercalated cells of CCDs dissected from alkali-loaded rabbits perfused in vitro. beta-Intercalated cells were identified by demonstrating the presence of an apical anion exchanger (cell alkalinization in response to removal of lumen Cl-). After 180 min of perfusion to permit decrease of endogenous cAMP, acute addition of 0.1 mM 8-bromo-cAMP or 1 microM isoproterenol to the bath caused a transient cellular alkalinization (> 0.20 pH units). In the symmetrical absence of either Na+, HCO3-, or Cl-, cAMP produced no change in pHi. Basolateral dihydrogen 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (0.1 mM) for 15 min before cAMP addition also prevented this alkalinization. In contrast to the response of cells from alkali-loaded rabbits, addition of basolateral cAMP to CCDs dissected from normal rabbits resulted in an acidification of beta-intercalated cells (approximately 0.20 pH units). The present studies demonstrate the importance of the in vivo acid-base status of the animal in the regulation of CCD HCO3- secretion by beta-intercalated cells. The results identify the possible existence of a previously unrecognized Na(+)-dependent Cl-/HCO3- exchanger on the basolateral membrane of beta-intercalated cells in alkali-loaded rabbits.

Carbonic anhydrase and proton secretion in turtle bladder mitochondrial-rich cells

1991 ◽  
Vol 260 (3) ◽  
pp. F443-F458
Author(s):  
C. Fritsche ◽  
J. G. Kleinman ◽  
J. L. Bain ◽  
R. R. Heinen ◽  
D. A. Riley
Keyword(s):  
Carbonic Anhydrase ◽  
Acid Base ◽  
Proton Secretion ◽  
Turtle Bladder ◽  
Acid Base Status ◽  
Reduced Density

Bladders from actively feeding turtles were processed for carbonic anhydrase (CA) cytochemically. CA-positive cells were identified as microplicated (MP) cells, microvillated (MV) cells, and subluminal (SL) cells. After acute enhancement of H+ secretion with 5% CO2, MP cells displayed extensive microplicae and a reduced density of apical subplasmalemmal vesicles, and they were CA reactive throughout a large part of the cytoplasm including the microplicae. After acute inhibition of H+ secretion with a pH 4.5 mucosal bath, CA staining was excluded from the microplicae and apical subplasmalemmal region of most MP cells, whereas microplicae varied from extensive to reduced, and subapical vesicle density remained elevated. MV cells were characterized by basolateral staining with sparing of the MV and apical subplasmalemmal region in all settings except 1) after 5% CO2 and 2) when MV cells were found in areas in which MP cells were stained to the lumen. These results indicate that CA is active at the site of H+ secretion in MP cells and is correlated with the acute acid-base status of the bladder.

Role of iNOS and eNOS in modulating proximal tubule transport and acid-base balance

2002 ◽  
Vol 283 (4) ◽  
pp. F658-F662 ◽  
Author(s):  
Tong Wang
Keyword(s):  
Proximal Tubule ◽  
Knockout Mice ◽  
Proximal Tubules ◽  
Wild Type ◽  
Acid Base Balance ◽  
Acid Base ◽  
Base Balance ◽  
Acid Base Status ◽  
Inos Knockout Mice ◽  
Oxide Synthase

Our laboratory has previously shown that mice lacking neuronal nitric oxide synthase (nNOS) are defective in fluid absorption ( J v) and HCO[Formula: see text]absorption ( J HCO3) in the proximal tubule and develop metabolic acidosis. The present study examined the transport of fluid and HCO[Formula: see text] in the proximal tubule and acid-base status in mice lacking two other isoforms of NOS, inducible NOS (iNOS) and endothelial NOS (eNOS). Proximal tubules were microperfused in situ in wild-type and NOS knockout mice by methods previously described (Wang T, Yang C-L, Abbiati T, Schultheis PJ, Shull GE, Giebisch G, and Aronson PS. Am J Physiol Renal Physiol 277: F298–F302, 1999). [3H]inulin and total CO2 concentrations were measured in the perfusate and collected fluid, and net J v and J HCO3 were analyzed. These data show that J HCO3 was 35% lower (71.7 ± 6.4 vs. 109.9 ± 7.3 pmol · min−1 · mm−1, n = 13, P < 0.01) and J v was 38% lower (0.95 ± 0.15 vs. 1.54 ± 0.17 nl · min−1 · mm−1, n = 13, P < 0.05) in iNOS knockout mice compared with their wild-type controls. Addition of the iNOS-selective inhibitor l- N 6-(1-iminoethyl) lysine, reduced both J v and J HCO3 significantly in wild-type, but not in iNOS knockout, mice. In contrast, both J HCO3(93.3 ± 7.9 vs. 110.6 ± 6.18 pmol · min−1 · mm−1) and J v (1.56 ± 0.17 vs. 1.55 ± 0.16 nl · min−1 · mm−1) did not change significantly in eNOS knockout mice. These results indicated that iNOS upregulates Na+ and HCO[Formula: see text]transport, whereas eNOS does not directly modulate Na+ and HCO[Formula: see text] transport in the kidney proximal tubules.

AE4 is a DIDS-sensitive Cl−/HCO 3 − exchanger in the basolateral membrane of the renal CCD and the SMG duct

2002 ◽  
Vol 283 (4) ◽  
pp. C1206-C1218 ◽  
Author(s):  
Shigeru B. H. Ko ◽  
Xiang Luo ◽  
Henrik Hager ◽  
Alexandra Rojek ◽  
Joo Young Choi ◽  
...  
Keyword(s):  
Collecting Duct ◽  
Basolateral Membrane ◽  
Rabbit Kidney ◽  
Intercalated Cells ◽  
Cortical Collecting Duct ◽  
Acid Base ◽  
Specific Expression ◽  
Hek 293 ◽  
Acid Base Status ◽  
Species Specific

The renal cortical collecting duct (CCD) plays an important role in systemic acid-base homeostasis. The β-intercalated cells secrete most of the HCO[Formula: see text], which is mediated by a luminal, DIDS-insensitive, Cl−/HCO[Formula: see text] exchange. The identity of the luminal exchanger is a matter of debate. Anion exchanger isoform 4 (AE4) cloned from the rabbit kidney was proposed to perform this function (Tsuganezawa H et al. J Biol Chem 276: 8180–8189, 2001). By contrast, it was proposed (Royaux IE et al. Proc Natl Acad Sci USA 98: 4221–4226, 2001) that pendrin accomplishes this function in the mouse CCD. In the present work, we cloned, localized, and characterized the function of the rat AE4. Northern blot and RT-PCR showed high levels of AE4 mRNA in the CCD. Expression in HEK-293 and LLC-PK1 cells showed that AE4 is targeted to the plasma membrane. Measurement of intracellular pH (pHi) revealed that AE4 indeed functions as a Cl−/HCO[Formula: see text] exchanger. However, AE4 activity was inhibited by DIDS. Immunolocalization revealed species-specific expression of AE4. In the rat and mouse CCD and the mouse SMG duct AE4 was in the basolateral membrane. By contrast, in the rabbit, AE4 was in the luminal and lateral membranes. In both, the rat and rabbit CCD AE4 was in α-intercalated cells. Importantly, localization of AE4 was not affected by the systemic acid-base status of the rats. Therefore, we conclude that expression and possibly function of AE4 is species specific. In the rat and mouse AE4 functions as a Cl−/HCO[Formula: see text] exchanger in the basolateral membrane of α-intercalated cells and may participate in HCO[Formula: see text] absorption. In the rabbit AE4 may contribute to HCO[Formula: see text] secretion.

Roles of gill and red cell carbonic anhydrase in elasmobranch HCO3- and CO2 excretion

1987 ◽  
Vol 253 (3) ◽  
pp. R450-R458 ◽  
Author(s):  
E. R. Swenson ◽  
T. H. Maren
Keyword(s):  
Carbonic Anhydrase ◽  
Respiratory Acidosis ◽  
Red Cell ◽  
Acid Base ◽  
Terrestrial Vertebrates ◽  
Carbonic Anhydrase Inhibition ◽  
Normal Metabolism ◽  
Acid Base Status ◽  
Erythrocyte Carbonic Anhydrase ◽  
Co2 Elimination

We studied the roles of gill and erythrocyte carbonic anhydrase in normal CO2 transfer (metabolic CO2 elimination) and in HCO3- excretion during metabolic alkalosis in the resting and swimming dogfish shark, Squalus acanthias. Gill carbonic anhydrase was selectively inhibited (greater than 98.5%) by 1 mg/kg benzolamide, which caused no physiologically significant red cell carbonic anhydrase inhibition (approximately 40%). Enzyme in both tissues was inhibited by 30 mg/kg methazolamide (greater than 99%). Both drugs caused equivalent reductions in HCO3- excretion following an infusion of 9 mmol/kg NaHCO3 as measured by the rate of fall in plasma HCO3- and by transfer into seawater. Methazolamide (red cell and gill carbonic anhydrase inhibition) caused a respiratory acidosis in fish with normal acid-base status, whereas benzolamide (gill carbonic anhydrase inhibition) did not. The only effect observed with benzolamide in these fish was a small elevation in plasma HCO3-. These findings, taken together, suggest that red cell carbonic anhydrase is required for normal metabolic CO2 elimination by the gill. Although carbonic anhydrase is located in the respiratory epithelium, it appears to have no quantitative role in transfer of metabolic CO2 to the environment, a pattern similar to all terrestrial vertebrates. However, carbonic anhydrase in the gill is crucial to this organ's function in acid-base regulation, both in the excretion of H+ or HCO3- generated in normal metabolism and in various acid-base disturbances.

Relative effects of carbonic anhydrase infusion or inhibition on carbon dioxide transport and acid-base status in the sea lamprey Petromyzon marinus following exercise

1996 ◽  
Vol 199 (4) ◽  
pp. 933-940
Author(s):  
B Tufts ◽  
S Currie ◽  
J Kieffer
Keyword(s):  
Carbon Dioxide ◽  
Carbonic Anhydrase ◽  
Venous Blood ◽  
Extracellular Fluid ◽  
Respiratory Acidosis ◽  
Acid Base ◽  
Carbon Dioxide Transport ◽  
Co2 Transport ◽  
Arterial Blood ◽  
Acid Base Status

In vivo experiments were carried out to determine the relative effects of carbonic anhydrase (CA) infusion or inhibition on carbon dioxide (CO2) transport and acid-base status in the arterial and venous blood of sea lampreys recovering from exhaustive exercise. Infusion of CA into the extracellular fluid did not significantly affect CO2 transport or acid-base status in exercised lampreys. In contrast, infusion of the CA inhibitor acetazolamide resulted in a respiratory acidosis in the blood of recovering lampreys. In acetazolamide-treated lampreys, the post-exercise extracellular pH (pHe) of arterial blood was significantly lower than that in the saline-infused (control) lampreys. The calculated arterial and venous partial pressure of carbon dioxide (PCO2) and the total CO2 concentration in whole blood (CCO2wb) and red blood cells (CCO2rbc) during recovery in the acetazolamide-infused lampreys were also significantly greater than those values in the saline-infused control lampreys. These results suggest that the CO2 reactions in the extracellular compartment of lampreys may already be in equilibrium and that the access of plasma bicarbonate to CA is probably not the sole factor limiting CO2 transport in these animals. Furthermore, endogenous red blood cell CA clearly has an important role in CO2 transport in exercising lampreys.

Effects of carbonic anhydrase inhibition on the acid base status in lamprey and trout

1995 ◽  
Vol 99 (2) ◽  
pp. 241-248 ◽  
Author(s):  
Raymond P. Henry ◽  
Robert G. Boutilier ◽  
Bruce L. Tufts
Keyword(s):  
Carbonic Anhydrase ◽  
Acid Base ◽  
Carbonic Anhydrase Inhibition ◽  
Acid Base Status

Sodium, chloride, and bicarbonate movement from plasma to cerebrospinal fluid in cats

1975 ◽  
Vol 228 (3) ◽  
pp. 673-683 ◽  
Author(s):  
BP Vogh ◽  
TH Maren
Keyword(s):  
Cerebrospinal Fluid ◽  
Carbonic Anhydrase ◽  
Choroid Plexus ◽  
Rate Constants ◽  
Secretory Cells ◽  
Acid Base ◽  
Rapid Exchange ◽  
Primary Signal ◽  
Carbonic Anhydrase Inhibition ◽  
Acid Base Status

Rate constants have been determined for the entry of 22Na+, 36Cl minus, and H14CO3- into CSF from plasma in cats during changes in Pco2 with and without inhibition of carbonic anhydrase. The application of these rate constants to movement of unlabeled electrolytes suggests that Na+ and Cl minus enter CSF by a one-way flux into newly formed fluid, but that entering HCO3-is involved both in net accumulation in new fluid and in rapid exchange with existing HCO3-. The entering HCO3-ions are not transferred from plasma but are formed in secretory cells from dissolved CO2. The exchange component of HCO3-entry is Pco2-dependent; entry of Na+ and Cl minus is not; hence net rate of HCO3-formation estimated by difference between Na+ and Cl minus is not Pco2 dependent. The net rate of HCO3-formation lies within the availability of CO2 from blood flow to choroid plexus but is not necessarily limited to this tissue. When carbonic anhydrase is inhibited, the net rate of formation of HCO3-is close to the calculated uncatalyzed rate expected for choroid plexus. The entry of all three ions is reduced by carbonic anhydrase inhibition, but the enzyme does not seem to provide the primary signal for alteration of CSF acid-base status. Regulation of CSF pH appears to be achieved through changes in HCO3-concentration that occur subsequent to the secretion of HCO3--rich new fluid.

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