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dc.contributor.advisorBrendel, Klausen_US
dc.contributor.authorSILBER, PAUL MICHAEL.
dc.creatorSILBER, PAUL MICHAEL.en_US
dc.date.accessioned2011-10-31T16:58:40Z
dc.date.available2011-10-31T16:58:40Z
dc.date.issued1987en_US
dc.identifier.urihttp://hdl.handle.net/10150/184097
dc.description.abstractIt is well known that a variety of toxicants can cause damage to the renal proximal tubule. However, the early pathogenesis of these deleterious interactions between a toxicant and this region of the nephron remain poorly understood. Thus, the purpose of this research was to attempt to answer three interrelated questions. First, what are the earliest changes in kidney function and structure after administration of tubule toxicants in vivo? Secondly, how do these structural/functional alterations change over time? Finally, are certain indicators of renal "dysfunction" more sensitive then others to the early stages of proximal tubule injury? The basic experimental approach consisted of injecting laboratory animals with a selective proximal tubule toxicant, and then collecting blood and/or urine at several timepoints after dosing; a variety of renal function indicators were evaluated at each of these timepoints. These included blood urea nitrogen (BUN), the glomerular filtration rate (GFR), and the excretion of glucose, protein, salts, glutathione, enzymes, and other endogenous molecules into the urine. At the termination of the exposure period the kidneys were evaluated histopathologically, and were also assayed for levels of specific enzymes and glutathione. Enzyme histochemistry was used to visualize changes in renal enzyme distribution, and protein electrophoretic methods permitted quantification of urinary proteins. These studies showed that specific markers of renal dysfunction were more sensitive to acute proximal tubule injury than other indicators. Specifically, the urinary excretion of proteins and the brush border membrane marker γ-glutamyl transpeptidase (GGT) were the best indicators of proximal tubule injury. Glucosuria, lysozymuria, and glutathionuria were all less sensitive markers, and changes in BUN or GFR were the poorest indicators of acute proximal tubule injury. These results indicated that the brush border membrane is one of the most susceptible regions of the proximal tubule to acute renal injury. Analysis of urinary protein electrophoresis patterns and kidney histopathology confirmed this hypothesis. This research also demonstrated the progression of the toxicant-tubule interaction over time, and showed that both tubule structure and function may be altered within minutes of administering a nephro-toxicant.
dc.language.isoenen_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.subjectKidney tubules -- Wounds and injuries.en_US
dc.subjectRenal tubular transport, Disorders of.en_US
dc.subjectKidneys.en_US
dc.subjectRenal pharmacology.en_US
dc.titleEARLY INDICATION AND PATHOGENESIS OF RENAL PROXIMAL TUBULE INJURY (ENZYMURIA)en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.identifier.oclc698474758en_US
thesis.degree.grantorUniversity of Arizonaen_US
thesis.degree.leveldoctoralen_US
dc.contributor.committeememberGandolfi, Jayen_US
dc.contributor.committeememberWright, Steveen_US
dc.contributor.committeememberHalpert, Jimen_US
dc.identifier.proquest8712911en_US
thesis.degree.disciplinePharmacology & Toxicologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.namePh.D.en_US
dc.description.noteThis item was digitized from a paper original and/or a microfilm copy. If you need higher-resolution images for any content in this item, please contact us at repository@u.library.arizona.edu.
dc.description.admin-noteOriginal file replaced with corrected file July 2023.
refterms.dateFOA2018-08-22T15:42:39Z
html.description.abstractIt is well known that a variety of toxicants can cause damage to the renal proximal tubule. However, the early pathogenesis of these deleterious interactions between a toxicant and this region of the nephron remain poorly understood. Thus, the purpose of this research was to attempt to answer three interrelated questions. First, what are the earliest changes in kidney function and structure after administration of tubule toxicants in vivo? Secondly, how do these structural/functional alterations change over time? Finally, are certain indicators of renal "dysfunction" more sensitive then others to the early stages of proximal tubule injury? The basic experimental approach consisted of injecting laboratory animals with a selective proximal tubule toxicant, and then collecting blood and/or urine at several timepoints after dosing; a variety of renal function indicators were evaluated at each of these timepoints. These included blood urea nitrogen (BUN), the glomerular filtration rate (GFR), and the excretion of glucose, protein, salts, glutathione, enzymes, and other endogenous molecules into the urine. At the termination of the exposure period the kidneys were evaluated histopathologically, and were also assayed for levels of specific enzymes and glutathione. Enzyme histochemistry was used to visualize changes in renal enzyme distribution, and protein electrophoretic methods permitted quantification of urinary proteins. These studies showed that specific markers of renal dysfunction were more sensitive to acute proximal tubule injury than other indicators. Specifically, the urinary excretion of proteins and the brush border membrane marker γ-glutamyl transpeptidase (GGT) were the best indicators of proximal tubule injury. Glucosuria, lysozymuria, and glutathionuria were all less sensitive markers, and changes in BUN or GFR were the poorest indicators of acute proximal tubule injury. These results indicated that the brush border membrane is one of the most susceptible regions of the proximal tubule to acute renal injury. Analysis of urinary protein electrophoresis patterns and kidney histopathology confirmed this hypothesis. This research also demonstrated the progression of the toxicant-tubule interaction over time, and showed that both tubule structure and function may be altered within minutes of administering a nephro-toxicant.


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