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Abstract: SA-PO083

The Role and Mechanism of Cyclophilin A in Cisplatin-Induced AKI

Session Information

  • AKI: Mechanisms - III
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Author

  • Tao, Li, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

Group or Team Name

  • Huazhong University of Science and Technology
Background

Nephrotoxicity is an important factor that limits the clinical use of cisplatin (CP), with approximately 20%-35% of patients suffering acute kidney injury (AKI) after treated with it. Cyclophilin A (CypA) is an intracellular receptor for the immunosuppressant cyclosporin A (CsA), and is reported to function in protein folding, signal transduction, inflammation, tumorigenesis and viral replication, while the specific role of CypA in CP-induced AKI still lacks in-depth research.

Methods

Here, we successfully established an AKI mice model via a single intraperitoneal injection of CP (25mg/kg), and a CsA derivative, NIM811, was used as an inhibitor of CpyA to treat the CP mice. In addition, vitro experiment was performed using HK-2 cells.

Results

In CP-AKI mouse model, the expression level of iCypA and eCypA were increased; Serum eCypA content positively correlated with SCr.Both the expression level of iCypA and eCypA were increased in HK-2 cells stimulated by CP.SCr was decreased significantly in CP-AKI mice treated with NIM811 and the pathological lesion of renal tubules was reduced.At the same time,NGAL and Cleaved-Caspase3 protein levels were decreased significantly as well as the number of TUNEL positive apoptotic cells was decreased.After CypA knockdown by siRNA transfection, Cleaved PARP1 and Cytc protein levels were decreased, the percentage of apoptotic cells was decreased, and cell viability was increased. In vitro, inhibition of CypA by NIM811 increased the cell viability, and decreased the levels of Cleaved PARP1 and Cytc protein.Cleaved PARP1 and Cleaved-Caspase3 protein levels were increased after rCypA was administrated in HK-2 cells.In the CP-AKI mouse model, increased CD147 expression was detected by IHC and WB. In vitro of CP-induced HK-2 cell injury, increased CD147 expression was found by WB assay.Knockdown of CypA could down-regulate the expression of CD147 in CP-stimulated HK-2 cells.Using siCD147 in HK-2 cells could down-regulate the increased expression of Cleaved PARP1 and Cytc protein levels as well as increase the cell viability.Knocking down CypA expression could alleviate the abnormalities of the AKT/AMPK/mTOR signaling pathway caused by CP stimulation.

Conclusion

CypA is increased and plays an injurious role in CP-induced AKI. And the underlying mechanism may attribute to promoting apoptosis by dysregulated CD147 and AKT/AMPK/mTOR signaling pathways.