Inhibition of CXCL1-CXCR2 axis ameliorates cisplatin-induced acute kidney injury by mediating inflammatory response.

Abstract

One of the limiting side effects of cisplatin use in cancer chemotherapy is nephrotoxicity. Inflammation is now believed to play a major role in the pathogenesis of cisplatin-induced acute kidney injury (AKI), and the mediators of inflammation contribute to it. CXCL1 was recently reported to be involved in renal physiology and pathology in ischemia mouse model; however, its roles and mechanisms in cisplatin-induced AKI are completely unknown. We observed that CXCL1 and CXCR2 expression in the kidney was markedly increased on day 7 after cisplatin treatment. Subsequently, we demonstrate that inhibition of CXCL1-CXCR2 signaling axis, using genetic and pharmacological approaches, reduces renal damage following cisplatin treatment as compared with control mice. Specifically, deficiency of CXCL1 or CXCR2 extensively preserved the renal histology and maintained the kidney functions after cisplatin treatment, which was associated with reduced expression of the pro-inflammatory cytokines and infiltration of neutrophils in the kidneys as compared. Furthermore, inhibition of CXCR2 by intragastric administration of repertaxin in mice with AKI reduces kidney injury associated with a reduction of inflammatory cytokines and neutrophils infiltration. Finally, we found that CXCL1/CXCR2 regulated cisplatin-induced inflammatory responses via the P38 and NF-κB signaling pathways in vitro and in vivo. In conclusion, our results indicate that CXCL1-CXCR2 signaling axis plays a crucial role in the pathogenesis of cisplatin-induced AKI through regulation of inflammatory response and maybe a novel therapeutic target for cisplatin-induced AKI.

• Authors: Peng Liu, Xinxiu Li, Weixing Lv, Zhaojun Xu
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 122 Pg. 109693 (Feb 2020) ISSN: 1950-6007 [Electronic] France
• PMID: 31812015 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Chemical References

• Chemokine CXCL1
• Cxcl1 protein, mouse
• Cxcr2 protein, mouse
• Cytokines
• NF-kappa B
• Receptors, Interleukin-8B
• Sulfonamides
• p38 Mitogen-Activated Protein Kinases
• Cisplatin
• reparixin

Topics

• Acute Kidney Injury (chemically induced, drug therapy, pathology)
• Animals
• Chemokine CXCL1 (deficiency, metabolism)
• Cisplatin (pharmacology)
• Cytokines (metabolism)
• Inflammation (drug therapy)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Models, Animal
• NF-kappa B (metabolism)
• Receptors, Interleukin-8B (deficiency, metabolism)
• Sulfonamides (pharmacology)
• p38 Mitogen-Activated Protein Kinases (metabolism)