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Kidney Week

Abstract: FR-PO117

Arginase 2 Is a Mediator of Cisplatin-Induced AKI Through Regulation of Macrophage Inflammatory Responses

Session Information

  • AKI: Mechanisms - II
    November 04, 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

Authors

  • Uchida, Yushi, Department of Internal Medicine, Fukuoka Dental College, Fukuoka, Japan
  • Torisu, Kumiko, Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
  • Aihara, Seishi, Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
  • Ooboshi, Hiroaki, Department of Internal Medicine, Fukuoka Dental College, Fukuoka, Japan
  • Nakano, Toshiaki, Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Background

Cisplatin is a classic and effective chemotherapeutic agent, but its application is limited by its nephrotoxicity. Cisplatin induces tubular damage followed by intensive infiltration of inflammatory cells such as macrophages. Arginine metabolism has emerged as a critical regulator of inflammatory responses in macrophages. Arginase 2 (ARG2) is an enzyme that degrades arginine, but its role in the inflammatory response of macrophages remains unclear. In this study, we investigated the inflammatory role of ARG2 in macrophages in cisplatin-induced acute kidney injury.

Methods

Male Arg2-/- and WT mice were treated with cisplatin (20 mg/kg) by intraperitoneal injection. After 3 days of treatment, mice were euthanized and the kidney and blood samples were collected for analysis. Bone marrow-derived macrophages (BMDMs) isolated from Arg2-/- and WT mice were stimulated with 100 ng/mL LPS for 24-hour to evaluate cytokine excretion (IL-6 and IL-1β). Primary proximal tubular epithelial cells (PTECs) isolated from Arg2-/- and WT mice were cultured under 100 µM cisplatin for 24-hour to evaluate tubular apoptosis induced by cisplatin.

Results

In vivo, ARG2 deficiency mitigated cisplatin-induced renal dysfunction (SCr: Arg2 -/- 1.01±0.11 mg/dL vs. WT 1.63±0.20 mg/dL, p<0.05). Cisplatin-induced tubular injury was also significantly attenuated in Arg2-/- mice as compared to WT mice based on histological analysis. The protein levels of cleaved caspase-3 and the number of TUNEL-positive cells in the kidneys of cisplatin-treated Arg2-/-mice were lower than those in the kidneys of WT mice. In vitro, Arg2-/- BMDMs had decreased secretion of proinflammatory cytokines as compared to WT BMDMs (IL-6: Arg2 -/- 1.96±0.23 ng/mL vs. WT 4.02±0.51 ng/dL; IL-1β: Arg2 -/- 3.38±0.44 ng/dL vs. WT 8.68±1.41 ng/mL, p<0.05), while there was no significant difference in tubular apoptosis caused by cisplatin between Arg2-/- and WT primary PTECs.

Conclusion

The deficiency of ARG2 significantly alleviated cisplatin-induced acute kidney injury. Our results suggested that ARG2 is a key mediator of macrophage inflammatory response, but is not directly involved in tubular apoptosis by cisplatin. Inhibition of ARG2 may be beneficial for the treatment of cisplatin-induced acute kidney injury by attenuating the inflammatory response of macrophages.

Funding

  • Government Support – Non-U.S.