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This dissertation, Osmotic Response Element Binding Protein (OREBP) is an Essential Regulator of Urine Concentrating Mechanism and Renal Protection by Ka-man, Amy, Lam, 林嘉敏, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Osmotic Response Element Binding Protein (OREBP) is an Essential Regulator of Urine Concentrating Mechanism and Renal Protection Submitted by Lam Ka Man Amy For the degree of Doctor of Philosophy at the University of Hong Kong In December 2004 OREBP (osmotic response element binding protein), also called TonEBP or NFAT-5, is thought to induce the expression of genes that increase the accumulation of several organic osmolytes so as to protect cells against hypertonic environment. To investigate the consequences of lacking OREBP activity, transgenic mice that overexpress OREBPdn (the dominant negative form of OREBP) specifically in the epithelial cells of the collecting tubules were generated. These mice produced excessive amount of dilute urine, indicating impairment in their urine concentration mechanism. This is most likely due to the reduced expression of aquaporin-2 (AQP2), urea transporter A-1 (UT-A1), and urea transporter A-2 (UT-A2) mRNAs in the kidneys of the transgenic mice. After water deprivation or the administration of 1-deamino-8-D-arginine vasopressin, the urine osmolality of the transgenic mice was significantly increased but not to the same extent as that of the non-transgenic littermates. The levels of expressions of AQP2 and UT-A1, but not UT-A2 mRNAs were increased to those of non-transgenic mice in the water deprivation condition, accounting for the partial restoration of their urine concentrating ability, and indicating that the vasopressin regulatory mechanism was not affected by OREBPdn. The independent regulation of urine concentration mechanism by OREBP and vasopressin was confirmed by the fact that treatment with a vasopressin receptor antagonist further reduced the urine osmolality of the trangenic mice under water ad libitum and water deprivation conditions. These data indicate that besides vasopressin, OREBP is another essential regulator of urine concentration mechanism. Further, the OREBPdn transgenic mice developed progressive hydronephrosis soon after weaning. The tubular cells in the kidneys of the 6-week- old or older transgenic mice were undergoing apoptosis and in cell culture they were shown to be more sensitive to osmotic stress. These results confirmed the osmoprotective function of OREBP implicated by the in vitro experiments. Our present studies indicate that OREBP is an essential regulator for renal water reabsorption and renal osmoprotection. These findings suggest that the cyclosporine A-induced nephrotoxicity might be partly contributed by its inhibition of OREBP activity. DOI: 10.5353/th_b3127402 Subjects: Genetic transcription - RegulationCarrier proteinsTranscription factorsUrineKidneys - PhysiologyTransgenic mice - Molecular genetics

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