Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P41181 (collecting duct)
 5,183 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Membrane-bound luminal carbonic anhydrase (CA) IV, by catalyzing the dehydration of carbonic acid into CO2 plus water, facilitates H+ secretion in the renal outer medullary collecting duct from the inner stripe (OMCDi). To examine the role of CA IV on H+ secretion, we measured net HCO3- transport in perfused OMCDi segments and examined the effect on transport of two extracellular CA inhibitors, benzolamide and F-3500, aminobenzolamide coupled to a nontoxic polymer, polyoxyethylene bis(acetic acid) [synthesized and kindly provided by C. Conroy and T. Maren (C. W. Conroy, G. C. Wynns, and T. H. Maren. Bioorg, Chem, 24: 262-272, 1996)]. These agents would inhibit only the luminal CA enzyme. Dose titration curves for net HCO3- flux were performed for each drug. Basal HCO3- absorptive flux was 12 pmol.min-1.mm-1 in control segments and significantly increased to 16 pmol.min-1.mm-1 in segments from 3-day acid-treated animals. The concentrations of benzolamide and F-3500 that inhibited HCO3- absorption by 50% were approximately 0.1 and approximately 5 microM, similar to the Ki for CA IV inhibition by these agents (0.2 and 4.0 microM, respectively; T. Maren, C. W. Conroy, G. C. Wynns, and D. R. Godman. J. Pharmacol. Exp. Ther. 280: 98-105, 1997). Adding exogenous CA to the inhibitor in the perfusate nearly restored basal HCO3- transport, suggesting that cytosolic CA II was not inhibited by these impermeant inhibitors. In OMCDi segments from acidotic rabbits, the concentrations of benzolamide and F-3500 that inhibited HCO3- absorption by 50% were 50 and 500 microM, respectively, > 100 times the Ki for CA IV inhibition and for inhibition of HCO3- transport in control tubules. Thus, in the OMCDi, doses of extracellular CA inhibitors that inhibited approximately 50% of CA IV activity also comparably inhibited HCO3- transport, indicating that H+ secretion depends in part on the availability of luminal CA IV activity. Acidosis substantially decreased the sensitivity of HCO3- transport to CA inhibition.
 ...
PMID:HCO3- absorption in rabbit outer medullary collecting duct: role of luminal carbonic anhydrase. 945 33

Carbonic anhydrase (CA) facilitates renal bicarbonate reabsorption and acid excretion. Cytosolic CA II catalyzes the buffering of intracellular hydroxyl ions by CO2, whereas membrane-bound CA IV catalyzes the dehydration of carbonic acid generated from the secretion of protons. Although CA II and IV are expressed in rabbit kidney, it is not entirely clear which segments express which isoforms. It was the purpose of this study to characterize the expression of CA II and CA IV mRNAs by specific segments of the nephron using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and to determine the effect of chronic metabolic acidosis on CA expression by those segments. Individual nephron segments (usually 1-2 mm) were isolated by microdissection and subjected to RT-PCR. Amplification was performed simultaneously for CA IV, CA II, and malate dehydrogenase (MDH), a housekeeping gene. The intensities of the PCR products were quantitated by densitometry. CA IV mRNA was expressed by S1 and S2 proximal tubules and by outer medullary collecting duct from inner stripe (OMCDi) and outer stripe and initial inner medullary collecting duct (IMCDi). CA II mRNA was expressed by S1, S2, and S3 proximal tubules, thin descending limb, connecting segment (CNT), and all collecting duct segments. Acid loading induced CA IV mRNA expression in S1 and S2 proximal tubules and in OMCDi and IMCDi. CA II mRNA was induced by acidosis in all three proximal segments and nearly all distal segments beginning with CNT. No upregulation of MDH mRNA expression occurred. These adaptive increases in CA II and IV mRNAs are potentially important in the kidney's adaptation to chronic metabolic acidosis.
 ...
PMID:Carbonic anhydrase II and IV mRNA in rabbit nephron segments: stimulation during metabolic acidosis. 948 20

DBA/2FG-pcy/pcy (D2-pcy) mice are a hereditary murine model of slowly progressive polycystic kidney disease (PKD) and characterized by the persistent excretion of acidic urine, in association with polyuria, after weaning. In this study, the activity of carbonic anhydrase (CA) and it histological distribution in the kidney of D2-pcy mice were investigated by immunohistochemistry. Significantly higher CA activity was detected in the cytosolic, but not membrane, fraction of kidney homogenates in 5-week-old D2-pcy mice than in age-matched, control DBA/2 (D2) mice, and a more rapid rate of urine acidification was noted in 11-week-old mice when acetazolamide, an inhibitor of the enzyme, was administered orally. By immunohistochemistry for the major renal CA isoenzyme (CA II), epithelial cells in the distal straight tubules and the cortical collecting ducts were stained intensely, whereas those of the proximal convoluted tubules had only weak and diffuse staining. The glomeruli, the proximal straight tubules and the ascending thin limb of Henle's loop were almost free from staining. In the cells lining cysts and/or dilated tubules, CA II activity was well preserved, although the staining intensity was considerably reduced in fully-flattened, lining cells of cysts, but no difference was found between D2-pcy and D2 mice in any segmental localization of renal CA II activity. From these results it seems that D2-pcy mice in the early stages of the cystic disease continue to secrete excess protons through the CA-mediated reaction that is stimulated for regulation of acid-base balance in the distal portion of the nephron and the collecting duct in kidney. It also suggests that monitoring urine pH may be useful in predicting the effects of early interventions on the progression of slowly developing renal cysts.
 ...
PMID:Renal carbonic anhydrase activity in DBA/2FG-pcy/pcy mice with inherited polycystic kidney disease. 1048 21

Carbonic anhydrase (CA) is an important enzyme in the kidney and facilitates renal acidification by catalvzing the reversible hydration of CO2 and the dehydration of bicarbonate. Currently, 14 isoforms of CA have been identified, of which CA II, CA IV, CA XII and possibly CA XIV are expressed by the kidney. Cytosolic CA II comprises -95% of renal CA, with the remainder being membrane-associated. CA II, while being nearly ubiquitous in the body, is also expressed by a large number of nephron segments, including proximal convoluted and straight tubules, thin descending limbs of Henle's loop, thick ascending limbs of Henle's loop in some species, intercalated cells of the cortical and medullary collecting ducts, and weakly in principal cells and inner medullary collecting ducts of some species; CA II is not found in glomeruli. Most membrane-associated CA is attributed to isoform IV, which is linked to the apical membrane via a glycosylphosphatidylinositol anchor; however, there is data showing that CA IV is also localized on the basolateral membranes of proximal tubule cells. How the basolateral form is linked to the membrane is not yet understood. CA IV is expressed on the luminal membrane of proximal convoluted and straight tubules, alpha-intercalated cells of cortical and medullary collecting ducts, and all cells of initial inner medullary collecting ducts. Another membrane isoform, CA XII, is also present in the kidney and probably situated in the basolateral membrane as a single-pass transmembrane protein. One study localizes CA XII to the distal nephron, while another places it in proximal tubules and inner medullary collecting ducts; confirmatory studies are needed for CA XII. The localization of CA XIV in the kidney is still under investigation. Functional studies clearly show the importance of apical and basolateral membrane CAs in mediating bicarbonate and fluid absorption in proximal tubules and of the apical membrane CA activity in mediating H+ secretion in the collecting duct. To establish other roles for CA in the kidney will require further kinetic, functional, immunolocalization and cloning studies.
 ...
PMID:Physiology and molecular biology of renal carbonic anhydrase. 1202 23

Acid-base balance is critical for normal life. Acute and chronic disturbances impact cellular energy metabolism, endocrine signaling, ion channel activity, neuronal activity, and cardiovascular functions such as cardiac contractility and vascular blood flow. Maintenance and adaptation of acid-base homeostasis are mostly controlled by respiration and kidney. The kidney contributes to acid-base balance by reabsorbing filtered bicarbonate, regenerating bicarbonate through ammoniagenesis and generation of protons, and by excreting acid. This review focuses on acid-base disorders caused by renal processes, both inherited and acquired. Distinct rare inherited monogenic diseases affecting acid-base handling in the proximal tubule and collecting duct have been identified. In the proximal tubule, mutations of solute carrier 4A4 (SLC4A4) (electrogenic Na+/HCO3--cotransporter Na+/bicarbonate cotransporter e1 [NBCe1]) and other genes such as CLCN5 (Cl-/H+-antiporter), SLC2A2 (GLUT2 glucose transporter), or EHHADH (enoyl-CoA, hydratase/3-hydroxyacyl CoA dehydrogenase) causing more generalized proximal tubule dysfunction can cause proximal renal tubular acidosis resulting from bicarbonate wasting and reduced ammoniagenesis. Mutations in adenosine triphosphate ATP6V1 (B1 H+-ATPase subunit), ATPV0A4 (a4 H+-ATPase subunit), SLC4A1 (anion exchanger 1), and FOXI1 (forkhead transcription factor) cause distal renal tubular acidosis type I. Carbonic anhydrase II mutations affect several nephron segments and give rise to a mixed proximal and distal phenotype. Finally, mutations in genes affecting aldosterone synthesis, signaling, or downstream targets can lead to hyperkalemic variants of renal tubular acidosis (type IV). More common forms of renal acidosis are found in patients with advanced stages of chronic kidney disease and are owing, at least in part, to a reduced capacity for ammoniagenesis.
 ...
PMID:Molecular Pathophysiology of Acid-Base Disorders. 3130 90


<< Previous 1 2