2. Academic Validation
  3. Cathelicidin-related antimicrobial peptide protects against ischaemia reperfusion-induced acute kidney injury in mice

Cathelicidin-related antimicrobial peptide protects against ischaemia reperfusion-induced acute kidney injury in mice

  • Br J Pharmacol. 2020 Jun;177(12):2726-2742. doi: 10.1111/bph.14998.
Li-Long Pan 1,  Wenjie Liang 2 3,  Zhengnan Ren 2 3,  Chunqing Li 4,  Yong Chen 5,  Wenying Niu 1,  Xin Fang 1,  Yanyan Liu 2 3,  Ming Zhang 2 3,  Julien Diana 6,  Birgitta Agerberth 7,  Jia Sun 2 3
Affiliations

Affiliations

  • 1 Wuxi School of Medicine, Jiangnan University, Wuxi, China.
  • 2 Laboratory of Nutritional Immunology and Translational Medicine, State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China.
  • 3 School of Food Science and Technology, Jiangnan University, Wuxi, China.
  • 4 Department of Nephrology, Affiliated Hospital of Jiangnan University, Wuxi, China.
  • 5 Department of Nephrology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China.
  • 6 Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 1151, Institute Necker-Enfants Malades (INEM), Centre National de la Recherche Scienctifique, Unité 8253, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
  • 7 Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, F68, Karolinska University Hospital Huddinge, Stockholm, Sweden.
PMID: 31976546 DOI: 10.1111/bph.14998
Abstract

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.

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