MDM2 is implicated in high-glucose-induced podocyte mitotic catastrophe via Notch1 signalling.
Hui TangChun-Tao LeiChen YePan GaoCheng WanShan ChenFang-Fang HeYu-Mei WangHua SuChun ZhangPublished in: Journal of cellular and molecular medicine (2017)
Podocyte injury and depletion are essential events involved in the pathogenesis of diabetic nephropathy (DN). As a terminally differentiated cell, podocyte is restricted in 'post-mitosis' state and unable to regenerate. Re-entering mitotic phase will cause podocyte disastrous death which is defined as mitotic catastrophe (MC). Murine double minute 2 (MDM2), a cell cycle regulator, is widely expressed in renal resident cells including podocytes. Here, we explore whether MDM2 is involved in podocyte MC during hyperglycaemia. We found aberrant mitotic podocytes with multi-nucleation in DN patients. In vitro, cultured podocytes treated by high glucose (HG) also showed an up-regulation of mitotic markers and abnormal mitotic status, accompanied by elevated expression of MDM2. HG exposure forced podocytes to enter into S phase and bypass G2/M checkpoint with enhanced expression of Ki67, cyclin B1, Aurora B and p-H3. Genetic deletion of MDM2 partly reversed HG-induced mitotic phase re-entering of podocytes. Moreover, HG-induced podocyte injury was alleviated by MDM2 knocking down but not by nutlin-3a, an inhibitor of MDM2-p53 interaction. Interestingly, knocking down MDM2 or MDM2 overexpression showed inhibition or activation of Notch1 signalling, respectively. In addition, genetic silencing of Notch1 prevented HG-mediated podocyte MC. In conclusion, high glucose up-regulates MDM2 expression and leads to podocyte MC. Notch1 signalling is an essential downstream pathway of MDM2 in mediating HG-induced MC in podocytes.
Keyphrases
- high glucose
- cell cycle
- endothelial cells
- cell proliferation
- diabetic nephropathy
- fluorescent probe
- gene expression
- living cells
- binding protein
- ejection fraction
- aqueous solution
- chronic kidney disease
- transcription factor
- end stage renal disease
- dna damage
- signaling pathway
- cell death
- oxidative stress
- cell cycle arrest
- induced apoptosis
- single cell
- peritoneal dialysis
- rectal cancer
- dna methylation