Journal
FASEB JOURNAL
Volume 34, Issue 1, Pages 1620-1636Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201901412R
Keywords
cell cycle; integrin beta 8; MDM2 membrane translocation; p53; TGF-beta 1
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Funding
- Program for HUST Academic Frontier Youth Team [2017QYTD20]
- National Natural Science Foundation of China [81570671, 81873602, 81770711]
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Acute kidney injury (AKI) is the leading cause of renal failure, and quite a few patients will advance to chronic kidney disease (CKD) in the long term. Here, we explore the roles and mechanisms of tubular epithelial cells (TECs) during repeated cisplatin (CP) induced AKI to CKD transition (AKI-CKD). Previously, we reported that murine double minute 2 (MDM2), an E3-ubiquitin ligase, is involved in tubulointerstitial fibrosis. However, whether tubular MDM2 is implicated in AKI-CKD is undefined. Currently, we confirmed that during AKI-CKD, MDM2 shifts from nucleus to cell membrane in TECs both in vivo and in vitro. Whereas regulating MDM2 distribution chemically or genetically has a prominent impact on tubular disorders. And then we investigated the mechanisms of the above findings. First, in the nucleus, repeated CP administration leads to MDM2 reduction with escalated p53 and cell cycle G2/M arrest. On the other hand, multiple CP treatment increases the level of membranous MDM2 with ensuing integrin beta 8 degradation and TGF-beta 1 activation. More interestingly, anchoring MDM2 on cell membranes can mimic the reduction of integrin beta 8 arousing by repeated CP exposure. Collectively, our findings provided the evidence that tubular MDM2 subcellular shuttling is involved in AKI-CKD through p53-G2/M arrest and integrin beta 8 mediated TGF-beta 1 activation.
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