MDM-2 in glomerular and interstitial kidney disease

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During the first funding period we described the p53-dependent pro-mitotic effects of MDM2 as well as, at first, the p53-independent pro-inflammatory effects. The MDM2 antagonist nutlin-3a dramatically improved experimental lupus nephritis, post-ischemic tubular necrosis, and focal-segmental glomerulosclerosis. However, MDM2 blockade impaired post-ischemic tubular-regeneration and had no effect on diabetic nephropathy. As we found MDM2 to be expressed predominantely in renal epithelial cells, we plan to use the second funding period to study the functional role of MDM2 in renal epithelia in more detail. We plan to 1. produce podocyte-, tubular cell, and monocyte-specific MDM2-deficient mice, 2 to characterize their spontaneous phenotype (homeostatic role of epithelial MDM2), 3. induce experimental models of glomerular and tubular injury (pathophysiological role of epithelial MDM2), and 4. to create each of these knockout mice in a cell type-specific p53+/+ or p53-/- manner to dissect the bifunctional role of MDM2. The analysis of all these mice will enable us to understand how renal epithelial cells handle stress signals in physiological and pathophysiological settings in terms of inflammation and regeneration. We speculate the constitutive expression of MDM2 to be an important element of renal epithelial homeostasis and repair.