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Podocyte Injury Causes Chronic Kidney Disease in the Ercc1 Deficient Mouse Model of Accelerated Aging

Wack, Kathryn E. (2014) Podocyte Injury Causes Chronic Kidney Disease in the Ercc1 Deficient Mouse Model of Accelerated Aging. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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In 2013, it was determined by the United States Renal Data System (USRDS) that 32% of the people over 60 had some form of chronic kidney disease (CKD)(1). CKD is often age-associated, but confounding factors make it difficult to separate age-related causes from other factors such as diabetes and hypertension. Animal models can be useful to evaluate aging nephropathy but are costly since they take years. The aim of this thesis was two-fold. First, I used the Ercc1 deficient mouse model of accelerated aging to test the hypothesis that unrepaired DNA damage can cause CKD, similar to that seen as a result of natural aging. Second, I tested the hypothesis that inherent podocyte damage due to Ercc1 deficiency causes the loss of kidney function associated with aging. In order to test this hypothesis, kidneys from the Ercc1-/Δ mouse, a model of a human progeria, and old wildtype (WT) (2-3 yrs) mice were characterized and compared to elucidate the time-course and extent of injury. At one month after birth, Ercc1-/Δ mice develop evidence of podocyte injury, autophagy induction, and a slightly elevated urine albumin-creatinine (ACR) ratio. Glomerular filtration rate (GFR) remained comparable to WT mice until 2 months, after which time albuminuria increased significantly, GFR decreased significantly, and podocytes began to display increased IKK expression and chronic NF-κB activation, as seen in old WT kidneys. At this same time, increased LC3 and p62 protein levels indicated a functional breakdown in autophagy. ICAM up-regulation in glomerular capillaries and tubule apical membranes occurred, followed by proximal tubule injury, an increase in myofibroblast-like cells and macrophage infiltration. A podocyte specific knock-out of Ercc1 was created and the results support the hypothesis that inherent podocyte injury drives age-related kidney pathologies. In contrast, a proximal tubule cell specific knock-out of Ercc1 showed no elevation in ACR, and no decrease in GFR throughout the time period tested. This thesis provides mechanistic information as to how aging nephropathy can occur over time as a result of endogenous DNA damage, and provides evidence that the podocyte should be a major target for therapeutic intervention.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Wack, Kathryn E. kew67@pitt.eduKEW67
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorStolz, Donna Bdstolz@pitt.eduDSTOLZ
Committee ChairKleyman, Thomaskleyman@pitt.eduKLEYMAN
Committee MemberNiedernhofer, Laura
Committee MemberLiu, Youhualiuy@upmc.eduYHLIU
Committee MemberIsenberg, Jeff Sjsi5@pitt.eduJSI5
Date: 7 August 2014
Date Type: Publication
Defense Date: 23 July 2014
Approval Date: 7 August 2014
Submission Date: 29 July 2014
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 148
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cell Biology and Molecular Physiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: aging, kidney, glomerulus, podocyte, chronic kidney disease, DNA damage
Date Deposited: 07 Aug 2014 13:41
Last Modified: 19 Dec 2016 14:42


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