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

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