Role and Mechanisms of Epithelial Injury in Diabetic Nephropathy

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DESCRIPTION (provided by applicant): Glucotoxicity, lipotoxicity, advanced glycation end products (AGE), and reactive oxygen species (ROS) have emerged as important mediators of diabetes-induced tissue injury. However, the precise cellular targets and molecular mechanisms by which these mediators cause cellular injury in the kidney remain poorly defined. Both, glomerular (podocytes) and tubular epithelial cells are now emerging as important targets for diabetes-induced injury in diabetic nephropathy (DN). Thus, podocyte depletion has been described recently in humans with type 1 (T1DM) and type 2 (T2DM) diabetes, and is considered a strong predictor for the development of proteinuria. In addition, tubular epithelial apoptosis and epithelial-mesenchymal transition (EMT) may underlie the initiation of tubulointerstitial progression of DN. We present preliminary results that provide a compelling rationale to focus our research program on investigating the emerging role and mechanisms of epithelial cell injury in DN. Specifically, we will test two novel hypotheses: 1. The peroxisomal membrane proteins Mpv17l and/or Mpv17 are essential regulators of antioxidant defenses in glomerular podocytes and protect against diabetes-induced podocyte apoptosis and podocyte depletion (Bottinger, Mount Sinai); and 2. CD36 scavenger receptor for AGE and/or FFA is an essential mediator of AGE and/or FFA-induced tubular epithelial injury/apoptosis and tubulointerstitial progression of DN (Susztak, AECOM). The Specific Aims of this proposal are to test: 1. whether peroxisomal membrane proteins regulate antioxidant defense mechanisms in podocytes, and protect against ROS-mediated podocyte injury/apoptosis induced by diabetes 2. whether Mpv17-deficiency accelerates and increases podocyte apoptosis and depletion leading to progressive glomerulosclerosis and/or nodules in diabetic mouse models 3. which CD36-dependent intracellular pathways signal AGE and FFA induced tubular epithelial injury/apoptosis 4. whether proximal tubular overexpression of AGE binding proteins CD36 and RAGE leads to increased tubular epithelial injury/apoptosis and tubulointerstitial progression of DN in mice