Department of Endocrinology and Metabolism, The First Hospital of Jilin University, 71 Xinmin St., Changchun, Jilin 130021, China.
Department of Anesthesiology, The Second Hospital of Jilin University, 218 Ziqiang St., Changchun, Jilin 130041, China.
Biochim Biophys Acta Mol Cell Res. 2018 Aug;1865(8):1034-1045. doi: 10.1016/j.bbamcr.2018.04.011. Epub 2018 Apr 26.
Oxidative stress and P53 contribute to the pathogenesis of diabetic kidney disease (DKD). Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of cellular antioxidant defense system, is negatively regulated by P53 and prevents DKD. Recent findings revealed an important role of mouse double minute 2 (MDM2) in protection against DKD. However, the mechanism remained unclear. We hypothesized that MDM2 enhances NRF2 antioxidant signaling in DKD given that MDM2 is a key negative regulator of P53. The MDM2 inhibitor nutlin3a elevated renal P53, inhibited NRF2 signaling and induced oxidative stress, inflammation, fibrosis, DKD-like renal pathology and albuminuria in the wild-type (WT) non-diabetic mice. These effects exhibited more prominently in nutlin3a-treated WT diabetic mice. Interestingly, nutlin3a failed to induce greater renal injuries in the Nrf2 knockout (KO) mice under both the diabetic and non-diabetic conditions, indicating that NRF2 predominantly mediates MDM2's action. On the contrary, P53 inhibition by pifithrin-α activated renal NRF2 signaling and the expression of Mdm2, and attenuated DKD in the WT diabetic mice, but not in the Nrf2 KO diabetic mice. In high glucose-treated mouse mesangial cells, P53 gene silencing completely abolished nutlin3a's inhibitory effect on NRF2 signaling. The present study demonstrates for the first time that MDM2 controls renal NRF2 antioxidant activity in DKD via inhibition of P53, providing MDM2 activation and P53 inhibition as novel strategies in the management of DKD.
氧化应激和 P53 导致糖尿病肾病 (DKD) 的发病机制。核因子红细胞 2 相关因子 2 (NRF2) 是细胞抗氧化防御系统的主要调节因子，受 P53 的负调控，可预防 DKD。最近的研究结果揭示了鼠双微体 2 (MDM2) 在预防 DKD 中的重要作用。然而，其机制尚不清楚。我们假设 MDM2 通过增强 NRF2 抗氧化信号在 DKD 中发挥作用，因为 MDM2 是 P53 的关键负调节因子。MDM2 抑制剂 nutlin3a 提高了肾脏中的 P53，抑制了 NRF2 信号并诱导了氧化应激、炎症、纤维化、DKD 样肾脏病理学和白蛋白尿在野生型（WT）非糖尿病小鼠中。这些作用在 nutlin3a 处理的 WT 糖尿病小鼠中更为明显。有趣的是，nutlin3a 在糖尿病和非糖尿病条件下，均未能在 Nrf2 敲除（KO）小鼠中引起更大的肾脏损伤，表明 NRF2 主要介导了 MDM2 的作用。相反，P53 抑制剂 pifithrin-α 激活了肾脏 NRF2 信号和 Mdm2 的表达，减轻了 WT 糖尿病小鼠的 DKD，但在 Nrf2 KO 糖尿病小鼠中没有。在高葡萄糖处理的小鼠系膜细胞中，P53 基因沉默完全消除了 nutlin3a 对 NRF2 信号的抑制作用。本研究首次证明，MDM2 通过抑制 P53 来控制 DKD 中的肾脏 NRF2 抗氧化活性，为 DKD 的管理提供了 MDM2 激活和 P53 抑制的新策略。
