Abstract: SA-PO124
Cellular G2/M Arrest Induced by VPR in Kidney Promotes AKI or AKI-CKD Transition and Can Be Partially Rescued by Specific Small Molecule Inhibitors
Session Information
- AKI: Mechanisms - AKI-CKD Transition
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Chen, Yuqiang, Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China
- Xiao, Wenzhen, Mount Sinai School of Medicine, New York, New York, United States
- E, Jing, Ningxia People's Hospital, New York, New York, United States
- Wang, Niansong, Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China
- Lee, Kyung, Mount Sinai School of Medicine, New York, New York, United States
- He, John Cijiang, Mount Sinai School of Medicine, New York, New York, United States
Background
HIV-1 encodes an accessory protein named vpr that will damage renal cells. Podocyte damage and tubular epithelial cell injury may lead to proteinuria, impaired renal function and acute kidney injury (AKI). AKI can contribute critically to chronic kidney disease (CKD). Studies show that vpr plays an important role in cell injury and leads to AKI or AKI-CKD transition. Developing the strategies for AKI-CKD transition is urgently needed. But the cellular and molecular basis of AKI-CKD transition by vpr is very complex and largely unclear.
Methods
Pax8-rtta; TRE-vpr double transgenic mice were fed with DOX to overexpress vpr in tubular cells. Similarly, podocin-rtta; TRE-vpr were generated to overexpress vpr in podocyte. DOX induction were started at the age of 4 weeks and the induction periods were 8wks,18wks, 23wks and 28wks, respectively. To alleviate or reverse vpr related lesion，P53 inhibitor PFT- α or PLK 1 inhibitor BI 2536 was administrated by Peritoneal Injection for 4 weeks. Renal function and proteinuria were monitored. After sacrifice the mice, the renal cortex genes, proteins and histology are screened.
Results
Vpr in tubular cells led to proximal tubular cells injury, G2/M arrested cell, AKI and impaired renal function without proteinuria. Histopathological analysis indicated PTC injury and apoptosis, even interstitial fibrosis and secondary cyst formation and kidney enlargement in long-term induced mice, which indicated AKI-CKD transition. Vpr overexpression in podocyte led to massive podocyte injury, proteinuria and secondary reduced renal function. Dox withdrawal led to relative mild lesions and less AKI-CKD transition, which indicated vpr overexpression was responsible for those kidney lesions. P53 and PLK 1 activation were involved in vpr overexpression related G2/M arrest. Both inhibitors reduced P53 and PLK 1 level in vivo, and partially rescued tubular cell injury, proteinuria and renal function impairment, as well as AKI-CKD transition.
Conclusion
Our study demonstrates that vpr plays an important role in the pathogenesis of tubular epithelial cell and podocyte damage and subsequent AKI or AKI-CKD transition. P53 and PLK 1 inhibition are useful to relieve or rescue tubular cell injury, proteinuria and AKI-CKD transition in vpr induced damages.
Funding
- NIDDK Support