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

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 mgÁkg −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.Abbreviations: AG1478, inhibitor of EGFR; AKI, acute kidney injury; AMP, antimicrobial peptide; Cnlp −/− , CRAMP deficient; CRAMP, mouse cathelicidin-related antimicrobial peptide; E-cadherin, epithelial cadherin; I/R, ischaemia/reperfusion; LL-37, human cathelicidin; MPO, myeloperoxidase; NETs, neutrophil extracellular traps; NLRP3, nucleotide-binding domain leucine-rich repeat containing family, pyrin domain containing 3; PBS, phosphate buffer saline; RT-qPCR, real-time quantitative PCR; TUNEL, terminal deoxyribonucleotide transferase (TdT)-mediated dUTP nickend labelling; WT, wild type.Li-Long Pan Wenjie Liang and Zhengnan Ren contributed equally to this work.

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The Yin and Yang of Alarmins in Regulation of Acute Kidney Injury

“…A single cathelicidin is found in humans—hcAP18/LL-37 and rodents—cathelicidin-related antimicrobial peptide (CRAMP) ( 140 ). Cathelicidin expression was significantly downregulated in clinical AKI as well as in murine models ( 72 ). NLRP3 overactivation was discovered to be one of the major effects of this deficiency in cathelicidin that causes elevated inflammatory responses and apoptosis ( 141 ).…”

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