Understanding the amplified susceptibility of the aging kidney to acute injury : studies of N-cadherin and matrix matalloprotinases : a dissertation /
| Main Author: | |
|---|---|
| Format: | Thesis Book |
| Language: | English |
| Published: |
College Station, Tex. :
Texas A&M University System Health Science Center,
2008.
|
| Subjects: |
| Abstract: | ABSTRACT: The normal kidney loses about 25% of its mass with aging, and lost of renal mass corresponds to a decline in renal function. Aging is also associated with an increased incidence and severity of acute kidney injury (AKI). However, the molecular mechanisms(s) underlying the increased susceptibility to injury remain undefined. Our laboratory is interested in identifying critical changes that occur, and the mechanisms involved, to amplify the sensitivity of the aging kidney to acute injury. It is known that the renal cortical tubule region is more susceptible to AKI, expecially the proximal tubular epithelium. There is evidence to suggest that the tubular epithelial cells can undergo epithelial-to-mesenchymal transition (EMT), and therefore, much effort has focused on mechanisms underlying EMT. While the impact of aging on EMT is yet to be demonstrated, a number of genes that promote EMT process are also associated with aging, among which are N-cadherin and matrix metalloproteinases, which are the focus of this dissertation. N-cadherin is the predominant cadherin expressed in the adult proximal tubular epithelial cells and the expression is lost with aging as reported by our laboratory previously; whereas MMPs increased with aging and have been implicated in a number of renal pathophysiologies. The first part of these studies examined the hypotheis that promoter hypermethylation is the mechanism underlying the loss of N-cadherin in aging rat kidney. We provided evidence that methylation at CpG site in the promoter region of N-cadherin increases with aging, resulting in the progressive reduction of N-cadherin expression. We speculate that the loss of N-cadherin by methylation predisposes the kidney to injury, given that several nephropathies have been associated with the loss of cadherin function. This finding represents a novel mechanism of N-cadherin gene silencing, and it may have broader implications as a mechansim underlying aging of the kidney. The second part of this dissertatoin examined a causal relationship between MMP-9 and -13, and the increased susceptibility to AKI. Both MMP-9 and -13 are known to be upregulated with aging and have been implicated in many pathological conditions. While a role for MMPs in AKI is emerging, there is no clear link between specific MMPs and AKI. We examined the hypothesis that MMP-9 and -13 mediate the age-related increase susceptibility to cisplatin-induced AKI using wild type and knockout mice, and pharmacologic inhibition. Our data demonstrate a potential key role for MMP-13 in mediating renal epithelial injury induced by cisplatin, while it appears that MMP-9 is not involved. Further, the pathogenesis of cisplatin-induced AKI involves loss and/or cleavage of N-cadherin, and we speculate that the potential role of MMPs in AKI involves an inflammatory mechanism. The implication of MMP-13 in these studies presents a novel therapeutic target for successful interventions in AKI; the role of MMP-13 in AKI needs to be further explored. |
|---|---|
| Item Description: | Vita. "Major Subject: Medical Sciences". "Submitted to the Office of Research and Graduate Studies of The Texas A&M University System Health Science Center in partial fulfillment for the requirements for the degree of Doctor of Philosophy August 2008." Approved as to style and content by: Alan R. Parrish, Robert Burghardt, Warren Zimmer, Emily Wilson, Harris Granger. |
| Physical Description: | xiii, 111 leaves : illustrations ; 28 cm. |
| Bibliography: | Includes bibliographical references (leaves 99-110). |