核转录因子p65活化是糖尿病肾病(DN)足细胞损伤的重要因素。近年研究显示Sam68蛋白参与p65活化，但机制不详。p65失去IκBα抑制而进入细胞核是其活化的基本模式。预实验发现：敲低Sam68可阻断高糖诱导的足细胞p65活化，但不影响IκBα磷酸化，提示其活化p65存在其他路径。Sam68是精氨酸甲基转移酶PRMT1的甲基化底物，最近研究显示DN足细胞高表达PRMT1。我们新近发现：高糖增加Sam68蛋白不对称二甲基精氨酸(ADMA)修饰，抑制Sam68和p65核内结合，降低其修饰则促进与p65结合，抑制p65转录活性。因此，课题提出：PRMT1介导Sam68蛋白ADMA修饰，阻遏Sam68与p65核内结合，增强p65转录活性促进DN足细胞损伤。本研究通过转染、IP、基因突变等技术，获得PRMT1介导Sam68蛋白ADMA修饰活化p65的证据。项目有望为DN足细胞保护提供新理论和靶点。

Activation of nuclear transcription factor p65 is an important factor in podocyte injury in diabetic nephropathy (DN). Recent studies have shown that Sam68 protein is involved in p65 activation, but the mechanism is unknown. The basic mode of p65 activation is that it loses the inhibition of I-kappa B-alpha and enters the nucleus. Preliminary experiments showed that knockdown of Sam68 blocked the activation of p65 in podocytes induced by high glucose without affecting inhibitor protein IκBα phosphorylation, suggesting that Sam68 protein participates in the activation of p65 in podocytes, and there are other pathways. Sam68 protein is the methylation substrate of arginine methyltransferase PRMT1. A recent study demonstrated that PRMT1 was highly expressed in podocytes of DN. We recently found that high glucose increased the modification of asymmetric dimethylarginine (ADMA) of Sam68 protein, inhibited the nuclear binding between Sam68 and p65. Decreased ADMA level of Sam68 protein can significantly promote the binding of Sam68 and p65, and inhibit p65 transcriptional activity. Therefore, we suggest that ADMA modification of Sam68 protein mediated by PRMT1, inhibit nuclear binding between Sam68 and p65, thus enhance p65 transcriptional activity and promote podocyte injury in DN. In this study, the reliable evidences of p65 activation result from increased ADMA modification of Sam68 protein mediated by PRMT1 was obtained by transfection, IP, gene mutation and other techniques. This study is expected to provide new theory and targets for the protection of podocyte in DN.