ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: PO0224

A Novel Renoprotective Strategy: Upregulation of PD-L1 Expression Mitigates Cisplatin-Induced AKI

Session Information

  • AKI Mechanisms - 3
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Zhang, Jun, University of California, Davis, Davis, California, United States
  • Gu, Shenwen V., University of California, Davis, Davis, California, United States
  • Hsu, Ssu-Wei, University of California, Davis, Davis, California, United States
  • Chen, Ching-Hsien, University of California, Davis, Davis, California, United States
Background

Cisplatin is an effective chemotherapeutic agent against various types of cancers; however, the use of cisplatin is associated with a major side-effect of nephrotoxicity, resulting in acute kidney injury (AKI). Growing evidence suggests that programmed death-1(PD-1)/programmed death ligand (PD-L1) immune checkpoint signaling plays a critical role in mediating inflammatory responses and immune homeostasis. While PD-L1 has emerged as a promising target for immunotherapy, little is known concerning how PD-L1 is regulated. In this study, we aimed to determine the expression and contribution of PD-L1 in cisplatin-induced AKI.

Methods

PD-L1 expression in kidney cells and tissues were determined by immunohistochemistry (IHC), real-time polymerase chain reaction and western blot assays. PD-L1-containing lentiviruses were subcapsularly injected into the kidneys of mice. 7 days after the injection, mice were intraperitoneally treated with cisplatin for 3 days and subjected to kidney function tests. High-dimensional single-cell mass spectrometry was used to reveal immune profiling and discover the underlying immunological mechanisms of PD-L1 in an AKI mouse model.

Results

IHC staining of PD-L1 shows a significantly lower intensity of staining and less stained proximal tubule epithelial cells in cisplatin-exposed mice tissues than that in the PBS controls. Next, we demonstrate that cisplatin exposure decreased mRNA expression and protein levels of PD-L1 in primary renal proximal tubular epithelial cells and this inhibition appeared to be dose-dependent. Interestingly, we also find a decrease in PD-L1 expression with a concomitant increase in pro-inflammatory cytokines in response to cisplatin. Mass spectrometry analyses reveal cisplatin-induced multiple pro-inflammatory leukocytes infiltration in kidneys. Through genetically engineered kidney tissues in mice, ectopic expression PD-L1 in kidneys was able to suppress leukocytes infiltration and pro-inflammatory cytokines. In addition, both serum creatinine and blood urea nitrogen levels were significantly reduced in cisplatin-treated mice with PD-L1 overexpression.

Conclusion

Our data suggest a renoprotective effect of PD-L1 upregulation on cisplatin-induced AKI and also provide an alternative therapeutic strategy against nephrotoxicity.

Funding

  • Other U.S. Government Support