F4/80hi Resident Macrophages Contribute to Cisplatin-Induced Renal Fibrosis

Sophia M. Sears, Alexis A. Vega, Zimple Kurlawala, Gabrielle B. Oropilla, Austin Krueger, Parag P. Shah, Mark A. Doll, Robert Miller, Levi J. Beverly and Leah J. Siskind

Full article link: https://kidney360.asnjournals.org/content/early/2022/02/10/KID.0006442021

Key Points

  • Long-term impacts of cisplatin are understudied; this study is the first to examine the role of macrophages in cisplatin-induced fibrosis

  • Depletion of kidney resident macrophages ameliorated cisplatin-induced fibrosis while depletion of infiltrating macrophages had no effect

  • This study highlights a pathogenic role for kidney resident M2 macrophages in development of fibrosis with repeated nephrotoxic injury

Abstract Background: Cisplatin-induced kidney injury remains a major obstacle in utilizing cisplatin as a chemotherapeutic for solid-organ cancers. 30% of patients treated with cisplatin develop acute kidney injury (AKI), and even patients who do not develop AKI are at risk for long term declines in kidney function and development of chronic kidney disease (CKD). Modeling cisplatin-induced kidney injury in mice has revealed that repeated, low doses of cisplatin lead to development of kidney fibrosis. This model can be used to examine AKI-to-CKD transition processes. Macrophages play a role in some of these processes, including immune response, wound healing, and tissue remodeling. Depleting macrophage populations in the kidney reduced fibrosis development in other models of renal fibrosis. Methods: We used either C57BL/6 mice with a Ccr2 genetic knockout or liposome encapsulated clodronate (Clodrosome) to deplete macrophage populations during repeated, 9 mg/kg cisplatin treatments. We assessed how immune cell populations were altered in the blood and kidney of these mice and how these alterations impacted development of renal fibrosis and kidney injury. Results: We found that Clodrosome treatment decreased collagen deposition, myofibroblast accumulation, and inflammatory cytokine production, while Ccr2 genetic knockout had no effect on these markers following cisplatin treatment. Additionally, Ccr2-/- mice had decreased levels of F4/80lo infiltrating macrophages in the kidney following cisplatin treatments, but Clodrosome treatment depleted F4/80hi resident and CD206+ M2 macrophages. Conclusions: These data suggest that Clodrosome depletion of F4/80hi and M2 macrophages in the kidney attenuates development of renal fibrosis following repeated, low doses of cisplatin.