PMID- 31976546 OWN - NLM STAT- MEDLINE DCOM- 20210621 LR - 20221207 IS - 1476-5381 (Electronic) IS - 0007-1188 (Print) IS - 0007-1188 (Linking) VI - 177 IP - 12 DP - 2020 Jun TI - Cathelicidin-related antimicrobial peptide protects against ischaemia reperfusion-induced acute kidney injury in mice. PG - 2726-2742 LID - 10.1111/bph.14998 [doi] AB - BACKGROUND AND PURPOSE: Despite recent advances in understanding its pathophysiology, treatment of acute kidney injury (AKI) remains a major unmet medical need, and novel therapeutic strategies are needed. Cathelicidin-related antimicrobial peptide (CRAMP) with immunomodulatory properties has an emerging role in various disease contexts. Here, we aimed to investigate the role of CRAMP and its underlying mechanisms in AKI. EXPERIMENTAL APPROACH: The human homologue LL-37 and CRAMP were measured in blood samples of AKI patients and in experimental AKI mice respectively. Experimental AKI was induced in wild-type and CRAMP-deficient (Cnlp(-/-) ) mice by ischaemia/reperfusion (I/R). Therapeutic evaluation of CRAMP was performed with exogenous CRAMP (5 mg.kg(-1) , i.p.) treatment. KEY RESULTS: Cathelicidin expression was inversely related to clinical signs in patients and down-regulated in renal I/R-induced injury in mice. Cnlp(-/-) mice exhibited exacerbated I/R-induced renal dysfunction, aggravated inflammatory responses and apoptosis. Moreover, over-activation of the NLRP3 inflammasome in Cnlp(-/-) mice was associated with I/R-induced renal injury. Exogenous CRAMP treatment markedly attenuated I/R-induced renal dysfunction, inflammatory response and apoptosis, correlated with modulation of immune cell infiltration and phenotype. Consistent with Cnlp(-/-) mouse data, CRAMP administration suppressed renal I/R-induced NLRP3 inflammasome activation, and its renal protective effects were mimicked by a specific NLRP3 inhibitor CY-09. The reno-protective and NLRP3 inhibitory effects of CRAMP required the EGF receptor. CONCLUSION AND IMPLICATIONS: Our results suggest that CRAMP acts as a novel immunomodulatory mediator of AKI and modulation of CRAMP may represent a potential therapeutic strategy. CI - (c) 2020 The British Pharmacological Society. FAU - Pan, Li-Long AU - Pan LL AD - Wuxi School of Medicine, Jiangnan University, Wuxi, China. FAU - Liang, Wenjie AU - Liang W AD - Laboratory of Nutritional Immunology and Translational Medicine, State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China. AD - School of Food Science and Technology, Jiangnan University, Wuxi, China. FAU - Ren, Zhengnan AU - Ren Z AD - Laboratory of Nutritional Immunology and Translational Medicine, State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China. AD - School of Food Science and Technology, Jiangnan University, Wuxi, China. FAU - Li, Chunqing AU - Li C AD - Department of Nephrology, Affiliated Hospital of Jiangnan University, Wuxi, China. FAU - Chen, Yong AU - Chen Y AD - Department of Nephrology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China. FAU - Niu, Wenying AU - Niu W AD - Wuxi School of Medicine, Jiangnan University, Wuxi, China. FAU - Fang, Xin AU - Fang X AD - Wuxi School of Medicine, Jiangnan University, Wuxi, China. FAU - Liu, Yanyan AU - Liu Y AD - Laboratory of Nutritional Immunology and Translational Medicine, State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China. AD - School of Food Science and Technology, Jiangnan University, Wuxi, China. FAU - Zhang, Ming AU - Zhang M AD - Laboratory of Nutritional Immunology and Translational Medicine, State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China. AD - School of Food Science and Technology, Jiangnan University, Wuxi, China. FAU - Diana, Julien AU - Diana J AD - Institut National de la Sante et de la Recherche Medicale (INSERM), Unite 1151, Institute Necker-Enfants Malades (INEM), Centre National de la Recherche Scienctifique, Unite 8253, Universite Paris Descartes, Sorbonne Paris Cite, Paris, France. FAU - Agerberth, Birgitta AU - Agerberth B AD - Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, F68, Karolinska University Hospital Huddinge, Stockholm, Sweden. FAU - Sun, Jia AU - Sun J AUID- ORCID: 0000-0002-4874-1305 AD - Laboratory of Nutritional Immunology and Translational Medicine, State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China. AD - School of Food Science and Technology, Jiangnan University, Wuxi, China. LA - eng GR - 2019-YY-038/Jiangsu Province Qing Lan Project and Jiangsu Province "Six Summit Talents" Program/ GR - WX0303B010518180007PB/Wuxi Social Development Funds for International Science & Technology Cooperation/ GR - JUFSTR20180103/National First-Class Discipline Program of Food Science and Technology/ GR - JUSRP11866/Fundamental Research Funds for the Central Universities/ GR - Jiangsu Province Recruitment Plan for High-level, Innovative and Entrepreneurial Talents/ GR - 81573420/National Natural Science Foundation of China/ GR - 81973322/National Natural Science Foundation of China/ GR - 31570915/National Natural Science Foundation of China/ GR - 81870439/National Natural Science Foundation of China/ GR - 91642114/National Natural Science Foundation of China/ PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200212 PL - England TA - Br J Pharmacol JT - British journal of pharmacology JID - 7502536 RN - 0 (Antimicrobial Cationic Peptides) RN - 0 (Cathelicidins) SB - IM MH - *Acute Kidney Injury/drug therapy/prevention & control MH - Animals MH - *Antimicrobial Cationic Peptides MH - Apoptosis MH - Humans MH - Ischemia MH - Kidney MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Reperfusion MH - Cathelicidins PMC - PMC7236077 COIS- The authors have declared no competing interests. EDAT- 2020/01/25 06:00 MHDA- 2021/06/22 06:00 PMCR- 2021/06/01 CRDT- 2020/01/25 06:00 PHST- 2019/07/12 00:00 [received] PHST- 2019/12/31 00:00 [revised] PHST- 2020/01/02 00:00 [accepted] PHST- 2020/01/25 06:00 [pubmed] PHST- 2021/06/22 06:00 [medline] PHST- 2020/01/25 06:00 [entrez] PHST- 2021/06/01 00:00 [pmc-release] AID - BPH14998 [pii] AID - 10.1111/bph.14998 [doi] PST - ppublish SO - Br J Pharmacol. 2020 Jun;177(12):2726-2742. doi: 10.1111/bph.14998. Epub 2020 Feb 12.