MDM2 controls NRF2 antioxidant activity in prevention of diabetic kidney disease

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.

Inhibition of P53/miR‐34a improves diabetic endothelial dysfunction via activation of SIRT1

“…32,33 Not until recent years was P53 identified to play a pathogenic role in DM and its complications. P53 is highly expressed under diabetic condition, contributing to the pathogenesis of DM, 34,35 diabetic cardiomyopathy, 36 nephropathy 22,37 and peripheral artery disease. 38 Here we report the pathogenic effect of P53 on diabetic aortic endothelial dysfunction, with miR-34a to be the mediator.…”

“…To study the effect of P53/miR-34a inhibition on aortic endothelial dysfunction under DM, pifithrin-α (PFT-α, 1.1 mg/kg, intraperitoneally injected three times weekly 21,22 ; MedChem Express, Shanghai, China) or miR-34a-I (2 mg/kg, subcutaneously injected once weekly 23 ; Thermo Fisher, Shanghai, China) was delivered to the diabetic mice immediately after DM was confirmed, for 24 weeks. In order to investigate the role of SIRT1 in mediating miR-34a-I's action, the diabetic mice were treated with EX-527 (2 mg/kg, 24 intraperitoneally injected three times weekly; MedChem Express) in the presence of miR-34a-I, for 24 weeks.…”

“…To study the effect of P53/miR-34a inhibition on aortic endothelial dysfunction under DM, pifithrin-α (PFT-α, 1.1 mg/kg, intraperitoneally injected three times weekly 21,22 ; MedChem Express, Shanghai, China) or miR-34a-I (2 mg/kg, subcutaneously injected once weekly 23 ; Thermo Fisher, Shanghai, China) was delivered to the diabetic mice immediately after DM was confirmed, for 24 weeks. To study the effect of P53/miR-34a inhibition on aortic endothelial dysfunction under DM, pifithrin-α (PFT-α, 1.1 mg/kg, intraperitoneally injected three times weekly 21,22 ; MedChem Express, Shanghai, China) or miR-34a-I (2 mg/kg, subcutaneously injected once weekly 23 ; Thermo Fisher, Shanghai, China) was delivered to the diabetic mice immediately after DM was confirmed, for 24 weeks.…”

“…HG-stimulated ECs were co-treated with P53-siRNA (20 nmol/L5,28 ; GenePharma, Suzhou, Jiangsu, China), or PFT-α (20 μmol/L,22 MedChem Express), for 48 hours. To investigate the effect of miR-34a inhibition on inflammation and oxidative stress, HG-treated ECs were co-treated with miR-34a-I, in parallel with PFT-α, for 48 hours.The role of miR-34a in mediating P53's action was further tested using miR-34a mimic (miR-34a-M) in the presence of PFT-α, under the HG condition.…”

Targeting MDM2 for novel molecular therapy: Beyond oncology

“…Further, multi‐omics studies have shown that MDM2 plays an important role in the glomeruli and tubules of the DN kidneys, as indicated by reductions in the expression of two key metabolite biomarkers, 3‐methylcrotonylglycine and uracil, when mice were treated with nutlin‐3 . Guo et al have observed that MDM2 controls the antioxidant activity of nuclear factor erythroid 2‐related factor 2 in mice with diabetic kidney disease by inhibiting p53.…”