The role of MORG1 in diabetic nephropathy

我们在DFG支持的先前项目中鉴定了血管紧张素II通过AT 2受体诱导的新基因。这些基因之一是脯氨酰羟化酶3（PHD 3），其在缺氧诱导因子1 α（HIF-1a）的调节中起关键作用。使用酵母双杂交系统，我们筛选PHD 3的潜在结合伙伴，并确定MORG 1（丝裂原活化蛋白激酶组织者1）。 与此同时，我们使用同源重组技术产生了MORG 1基因敲除小鼠。虽然杂合的MORG 1 +/-表现出正常的表型，但纯合的MORG 1-/-突变在E10.5天是致命的。与从野生型（MORG 1 +/+）小鼠获得的肾小球相比，从MORG 1 +/-小鼠分离的肾小球具有较低的PHD 3酶活性。在肾缺血-再灌注模型中，与野生型小鼠相比，MORG 1 +/-小鼠具有更好的肾功能和更少的肾脏炎症（Hammerschaldet al. Am J Physiol Renal Physiol 297：F1273-87，2009）。体外研究揭示了血管紧张素II对MORG 1、PHD 3活性和HIF-1 α诱导的复杂的时间和细胞类型特异性调节（Bondeva等人，Am J Nephrol 35：442-455，2012）。第一个初步研究表明，糖尿病MORG 1 +/-小鼠在诱导糖尿病后4周，与糖尿病野生型小鼠相比，蛋白尿显着减少。本申请的目的是更好地理解MORG 1在调节HIF-1 α中的作用，以鉴定MORG 1启动子中的潜在调节元件，并阐明MORG 1在糖尿病肾病中的作用以及MORG 1表达的操纵是否可以是治疗选择。

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.