The role of MORG1 in diabetic nephropathy

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IWe identified in previous projects supported by the DFG novel genes induced by angiotensin II via AT2 receptors. One of these genes is prolylhydroxylase 3 (PHD3) that plays a pivotal role in the regulation of hypoxia inducible Factor 1 alpha (HIF-1a). Using yeast-two-hybrid systems, we screened for potential binding partners of PHD3 and identified MORG1 (mitogen-activated protein kinase organizer 1). In the meantime we have generated MORG1 knockout mice using homologous recombination technology. While heterozygous MORG1+/- exhibit a normal phenotype, the homozygous MORG1-/- mutation is lethal at day E 10.5. Glomeruli isolated from MORG1+/- mice have less PHD 3 enzyme activity compared to those obtained from wild-type (MORG1+/+) mice. MORG1+/- mice have a better renal function and less renal inflammation compared to wild-type mice in a renal ischemia-reperfusion model (Hammerschmidt et al. Am J Physiol Renal Physiol 297:F1273-87, 2009). In vitro studies revealed a complex time- and cell type specific regulation of MORG1, PHD3 activity and HIF-1a induction by Angiotensin II (Bondeva et al. Am J Nephrol 35:442-455, 2012). First pilot studies showed that diabetic MORG1+/- mice revealed significantly less proteinuria compared to diabetic wild-type mice 4 weeks after induction of diabetes. The aims of the present application are to better understand the role of MORG1 in regulation of HIF-1a, to identify potential regulatory elements in the MORG1 promoter, and to elucidate the role of MORG1 in diabetic nephropathy and whether manipulation of MORG1 expression may be a therapeutical option.