Increased susceptibility of aging kidney to ischemic injury, role of matrix metalloprotinases (MMPS) : a dissertation /
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| Format: | Thesis Book |
| Language: | English |
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[College Station, Tex.] :
[Texas A&M University System Health Science Center],
[2007]
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| Abstract: | ABSTRACT: Aging is associated with an increased incidence and severity of acute renal failure. However, the molecular mechanism(s) underlying the increased susceptibility to injury remain undefined. These experiments were designed to investigate the influence of age on the response of the kidney to ischemic and nephrotoxic challenge. Renal slices were prepared from young (5 month), aged ad libitim (aged-AL; 24 month) aged caloric restricted (aged-CR; 24 month) male Fischer 344 rats and subjected to ischemic stress (anoxia, 100% N₂) for 0-60 min and to cisplatin (2 mM, 4hr) challenge. As assessed by biochemical and histological evaluation, slices from aged-AL rats were more susceptible to injury than young counterparts. Importantly, caloric restriction attenuated the increased susceptibility to injury. In an attempt to identify the molecular pathway(s) underlying this response, microarray analysis was performed on tissued harvested from the same animals used for the functional analysis. RNA was isolated and the corresponding cDNA was hybridized to CodeLink(tm) Rat Whole Genome Bioarray slides. Subsequent gene expression analysis was performed using GeneSpring software. Using a 2-fold difference as a cut-off with two-sample t-test, the expression of 92 genes was changed during aging and was attenuated by caloric restriction. Four of these genes -cludin-7, kidney injury molecule-1, matrix metalloproteinase-7, and the alpha 1 subunit of the Na+K+-ATPase - were verified by quantitative RT-PCR. Given the emerging role of MMPs in ischemic renal injury, the renal mRNA expression of MMPs and their endogenous inhibitors, TIMPs (tissue inhibitor of metalloproteinases), were also examined in young, aged-AL and aged-CR rats. Interestingly, age-dependent increases in the expression of MMP-7, -9, -13, and -14 were seen, and these changes were attenuated by caloric restriction. The expression of TIMP-1, but not TIMP-2 or -3, was increased by aged and attenuated by caloric restriction. Changes in MMP expression gene expression were paralleled by an age-dependent increase in collagenase, gelatinase, and membrane type-MMP activity. Specific increase in MMP-7 and -9 activities were seen in urine and kidney tissue, respectively. These results suggest an association between the aged-related increase in susceptibility to injury and overexpression of select MMPs (-7, -9, -13, and -14) in the kidney, implying a therapeutic potential for inhibition of the MMPs in acute kidney injury. |
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| Item Description: | Vita. "Major Subject: Medical Sciences". "Submitted to the Graduate School of Biomedical Sciences of the Texas A&M Health Science Center in partial fulfillment for the requirements for the degree of Doctor of Philosophy May 2007." Approved as to style and content by: Alan R. Parish, William H. Griffith, Gerald D. Frye, Paul C. Brandt, Robert C. Burghardt, and Harris J. Granger. |
| Physical Description: | xi, 97 leaves : illustrations ; 28 cm. |
| Bibliography: | Includes bibliographical references (leaves 76-95). |