Open AccessMDM 2 is implicated in high‐glucose‐induced podocyte mitotic catastrophe via Notch1 signalling
Author(s) -
Tang Hui,
Lei ChunTao,
Ye Chen,
Gao Pan,
Wan Cheng,
Chen Shan,
He FangFang,
Wang YuMei,
Su Hua,
Zhang Chun
Publication year - 2017
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13253
Subject(s) - podocyte , mitosis , microbiology and biotechnology , mitotic catastrophe , gene silencing , cell cycle , cancer research , cell growth , podocalyxin , biology , chemistry , cell , kidney , endocrinology , genetics , gene , proteinuria
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 ( MDM 2), a cell cycle regulator, is widely expressed in renal resident cells including podocytes. Here, we explore whether MDM 2 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 MDM 2. 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 MDM 2 partly reversed HG ‐induced mitotic phase re‐entering of podocytes. Moreover, HG ‐induced podocyte injury was alleviated by MDM 2 knocking down but not by nutlin‐3a, an inhibitor of MDM 2‐p53 interaction. Interestingly, knocking down MDM 2 or MDM 2 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 MDM 2 expression and leads to podocyte MC . Notch1 signalling is an essential downstream pathway of MDM 2 in mediating HG ‐induced MC in podocytes.