Abstract: FR-PO604

P53 Mediates the Protective Effect of SRT2104 on Diabetic Kidney Disease

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Wu, Hao, The Second Hospital of Jilin University, Changchun, China
  • Wu, Junduo, The Second Hospital of Jilin University, Changchun, China
  • Zhou, Shengzhu, The Second Hospital of Jilin University, Changchun, China
Background

Silent mating type information regulation 2 homolog 1 (Sirt1) plays an important role in protection against diabetic kidney disease (DKD). Activation of Sirt1 by small molecules showed beneficial effects on experimental DKD. SRT2104 is a potent selective activator of Sirt1, and has been used in clinical trials, demonstrating both safety and tolerability. However, to date, the effect and mechanism of SRT2104 on DKD have remained unknown. P53 is an essential factor that induces the pathogenesis of DKD. Sirt1 deacetylates P53, leading to the inactivation of P53. Therefore, we hypothesize that SRT2104 inhibits P53 by activation of Sirt1, the effect of which ameliorates DKD.

Methods

Eight-week-old male C57BL/6 mice were induced to diabetes by streptozotocin, and were treated in the presence or absence of SRT2104, for a period of 24 weeks. To test whether or not P53 is required for SRT2104’s action, mouse mesangial cells (MMCs) were treated with high glucose in combination with SRT2104, in the presence or absence of P53 siRNA.

Results

The diabetic mice exhibited remarkable renal inflammation, oxidative damage, fibrosis, pathological remodeling and albuminuria. These effects were significantly ameliorated by SRT2104. SRT2014 restored Sirt1 protein level and activity, and inactivated P53 in the kidneys of the diabetic mice. Interestingly, despite the activation of Sirt1, SRT2104 completely lost the protective effects in the presence of P53 siRNA in high glucose-treated MMCs.

Conclusion

The present study demonstrates, for the first time, that SRT2104 prevents DKD, the effect of which may be mediated by P53.

Funding

  • Government Support - Non-U.S.