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    Changes in (calcium(2+))(i) and pH(i) in cultured rat proximal tubular epithelium following anoxia: An in vitro model for renal ischemia.

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    Author
    Chi, Wei-Ming
    Advisor
    Trump, Benjamin F.
    Date
    1993
    Type
    dissertation
    
    Metadata
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    Abstract
    This study tests the hypothesis that intracellular {dollar}pH\ (pH\sb{lcub}i{rcub}){dollar} and ionized cytosolic calcium ( (Ca{dollar}\sp{lcub}2+{rcub}{dollar}) {dollar}\sb{lcub}i{rcub}{dollar}) deregulation relate to reversible and irreversible responses to anoxia with and without inhibition of glycolysis. Effects of anoxia on (Ca{dollar}\sp{lcub}2+{rcub}{dollar}) {dollar}\sb{lcub}i{rcub}{dollar} were studied in cultured proximal tubular epithelial cells (PTE) correlated with mitochondrial function and cell viability. After 5 hours of exposure to oxygen-depleted medium, ATP slowly declined by 30% associated with minimal cell killing. When iodoacetic acid was added to the argon-bubbled perfusate, ATP decreased precipitously and was not measurable by 30 min. This was associated with 80% LDH release by 3 hr. Changes in (Ca{dollar}\sp{lcub}2+{rcub}{dollar}) {dollar}\sb{lcub}i{rcub}{dollar} exhibited three distinct phases. Phase 1 showed no change in (Ca{dollar}\sp{lcub}2+{rcub}{dollar}) {dollar}\sb{lcub}i{rcub}{dollar} for a variable time, was shortened dramatically by inhibition of glycolysis, and produced a rapid and uniform (Ca{dollar}\sp{lcub}2+{rcub}{dollar}) {dollar}\sb{lcub}i{rcub}{dollar} elevation after 30 minutes of hypoxia. Phase 2 was characterized by a rapid increase in (Ca{dollar}\sp{lcub}2+{rcub}{dollar}) {dollar}\sb{lcub}i{rcub}{dollar}. Phase 3 was characterized by buffering of Ca{dollar}\sp{lcub}2+{rcub}{dollar}-reflecting intrinsic buffering mechanisms in Ca{dollar}\sp{lcub}2+{rcub}{dollar}-overloaded cells. The rapid drop of (Ca{dollar}\sp{lcub}2+{rcub}{dollar}) {dollar}\sb{lcub}i{rcub}{dollar} upon reoxygenation suggests a shift of metabolism to mitochondrial respiration when the glycolytic capacity in PTE was depleted. Our data clearly demonstrate that (Ca{dollar}\sp{lcub}2+{rcub}{dollar}) {dollar}\sb{lcub}i{rcub}{dollar} elevation in PTE is not simply a postmortem event but an early change of anoxic injury. Loss of mitochondrial membrane potential accompanying elevated (Ca{dollar}\sp{lcub}2+{rcub}{dollar}) {dollar}\sb{lcub}i{rcub}{dollar} implies a deleterious effect of sustained high (Ca{dollar}\sp{lcub}2+{rcub}{dollar}) {dollar}\sb{lcub}i{rcub}{dollar} on mitochondria. Acidosis during ischemia has been recognized but the change in {dollar}pH\sb{lcub}i{rcub}{dollar} has not been reported in cultured PTE. Our results show that exposure to chemical anoxia causes the {dollar}pH\sb{lcub}\rm i{rcub}{dollar} to drop immediately, followed by spontaneous alkalinization. Immediately after this, {dollar}pH\sb{lcub}i{rcub}{dollar} continuously declined and remained low until rising moderately just before cell death. Parallel estimations of (Ca{dollar}\sp{lcub}2+{rcub}{dollar}) {dollar}\sb{lcub}i{rcub}{dollar} shows increase of (Ca{dollar}\sp{lcub}2+{rcub}{dollar}) {dollar}\sb{lcub}i{rcub}{dollar} as {dollar}pH\sb{lcub}i{rcub}{dollar} declined. Prolongation of intracellular acidosis and protection were produced by blocking the {dollar}\rm Na\sp+/H\sp+{dollar} exchange activity with amiloride. Monensin, on the other hand, accelerated anoxic cytotoxicity. The terminal {dollar}pH\sb{lcub}\rm i{rcub}{dollar} rise may represent a phenomenon of cell permeability and irreversible cell injury. Taken together, our data suggested that the cytoprotective effects of acidosis may be to counteract Ca{dollar}\sp{lcub}2+{rcub}{dollar}-dependent mechanisms of anoxic injury.
    Description
    University of Maryland, Baltimore. Pathology. Ph.D. 1993
    Keyword
    Health Sciences, Toxicology
    Chemistry, Biochemistry
    Health Sciences, Pathology
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/1617
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    Theses and Dissertations All Schools
    Theses and Dissertations School of Medicine

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