2. Academic Validation
  3. MDM2 controls NRF2 antioxidant activity in prevention of diabetic kidney disease

MDM2 controls NRF2 antioxidant activity in prevention of diabetic kidney disease

  • Biochim Biophys Acta Mol Cell Res. 2018 Aug;1865(8):1034-1045. doi: 10.1016/j.bbamcr.2018.04.011.
Weiying Guo 1,  Dan Tian 2,  Ye Jia 3,  Wenlin Huang 4,  Mengnan Jiang 5,  Junnan Wang 6,  Weixia Sun 7,  Hao Wu 8
Affiliations

Affiliations

  • 1 Department of Endocrinology and Metabolism, The First Hospital of Jilin University, 71 Xinmin St., Changchun, Jilin 130021, China.
  • 2 Department of Anesthesiology, The Second Hospital of Jilin University, 218 Ziqiang St., Changchun, Jilin 130041, China.
  • 3 Department of Nephrology, The First Hospital of Jilin University, 71 Xinmin St., Changchun, Jilin 130021, China.
  • 4 School of Science and Technology, Georgia Gwinnett College, Lawrenceville, GA 30043, USA.
  • 5 Department of Natural Pharmaceutical Chemistry, College of Pharmacology, Jilin University, 1163 Xinmin St., Changchun, Jilin 130021, China.
  • 6 Department of Cardiology, The Second Hospital of Jilin University, 218 Ziqiang St., Changchun, Jilin 130041, China.
  • 7 Department of Nephrology, The First Hospital of Jilin University, 71 Xinmin St., Changchun, Jilin 130021, China. Electronic address: sunwx@jlu.edu.cn.
  • 8 Department of Hand and Foot Surgery, The First Hospital of Jilin University, 71 Xinmin St., Changchun, Jilin 130021, China; Department of Translational Medicine, The First Hospital of Jilin University, 71 Xinmin St., Changchun, Jilin 130021, China. Electronic address: wuhaobaha@jlu.edu.cn.
PMID: 29704532 DOI: 10.1016/j.bbamcr.2018.04.011
Abstract

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.

Keywords

Diabetes; Diabetic nephropathy; Nrf2; Oxidative stress; P53.

Figures
Products