Cathelicidin-related Antimicrobial Peptide Protects Against Ischaemia Reperfusion-induced Acute Kidney Injury in Mice

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2020 Jan 25

PMID 31976546

Citations 17

Authors

Li-Long Pan

Wenjie Liang

Zhengnan Ren

Chunqing Li

Yong Chen

Wenying Niu

Xin Fang

Yanyan Liu

Ming Zhang

Julien Diana

Birgitta Agerberth

Jia Sun

Affiliations

Soon will be listed here.

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 , 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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References

Rekha R, Muvva S, Wan M, Raqib R, Bergman P, Brighenti S . Phenylbutyrate induces LL-37-dependent autophagy and intracellular killing of Mycobacterium tuberculosis in human macrophages. Autophagy. 2015; 11(9):1688-99. PMC: 4590658. DOI: 10.1080/15548627.2015.1075110. View

Bei Y, Pan L, Zhou Q, Zhao C, Xie Y, Wu C . Cathelicidin-related antimicrobial peptide protects against myocardial ischemia/reperfusion injury. BMC Med. 2019; 17(1):42. PMC: 6381635. DOI: 10.1186/s12916-019-1268-y. View

Gallo R, Hooper L . Epithelial antimicrobial defence of the skin and intestine. Nat Rev Immunol. 2012; 12(7):503-16. PMC: 3563335. DOI: 10.1038/nri3228. View

Soehnlein O, Wantha S, Simsekyilmaz S, Doring Y, Megens R, Mause S . Neutrophil-derived cathelicidin protects from neointimal hyperplasia. Sci Transl Med. 2011; 3(103):103ra98. PMC: 3246402. DOI: 10.1126/scitranslmed.3002531. View

Becknell B, Schwaderer A, Hains D, Spencer J . Amplifying renal immunity: the role of antimicrobial peptides in pyelonephritis. Nat Rev Nephrol. 2015; 11(11):642-55. DOI: 10.1038/nrneph.2015.105. View

Zhou X, Zhang W, Yao Q, Zhang H, Dong G, Zhang M . Exosome production and its regulation of EGFR during wound healing in renal tubular cells. Am J Physiol Renal Physiol. 2017; 312(6):F963-F970. PMC: 5495889. DOI: 10.1152/ajprenal.00078.2017. View

Deng B, Luo Y, Kang X, Li C, Morisseau C, Yang J . Epoxide metabolites of arachidonate and docosahexaenoate function conversely in acute kidney injury involved in GSK3β signaling. Proc Natl Acad Sci U S A. 2017; 114(47):12608-12613. PMC: 5703276. DOI: 10.1073/pnas.1705615114. View

Abed A, Toubas J, Kavvadas P, Authier F, Cathelin D, Alfieri C . Targeting connexin 43 protects against the progression of experimental chronic kidney disease in mice. Kidney Int. 2014; 86(4):768-79. DOI: 10.1038/ki.2014.108. View

Bao J, Sato K, Li M, Gao Y, Abid R, Aird W . PR-39 and PR-11 peptides inhibit ischemia-reperfusion injury by blocking proteasome-mediated I kappa B alpha degradation. Am J Physiol Heart Circ Physiol. 2001; 281(6):H2612-8. DOI: 10.1152/ajpheart.2001.281.6.H2612. View

10.

Zhang M, Wang X, Wang Y, Niu A, Wang S, Zou C . IL-4/IL-13-mediated polarization of renal macrophages/dendritic cells to an M2a phenotype is essential for recovery from acute kidney injury. Kidney Int. 2016; 91(2):375-386. PMC: 5548101. DOI: 10.1016/j.kint.2016.08.020. View

11.

Raup-Konsavage W, Wang Y, Wang W, Feliers D, Ruan H, Reeves W . Neutrophil peptidyl arginine deiminase-4 has a pivotal role in ischemia/reperfusion-induced acute kidney injury. Kidney Int. 2017; 93(2):365-374. PMC: 5794573. DOI: 10.1016/j.kint.2017.08.014. View

12.

Pan L, Liang W, Ren Z, Li C, Chen Y, Niu W . Cathelicidin-related antimicrobial peptide protects against ischaemia reperfusion-induced acute kidney injury in mice. Br J Pharmacol. 2020; 177(12):2726-2742. PMC: 7236077. DOI: 10.1111/bph.14998. View

13.

Alexander S, Kelly E, Mathie A, Peters J, Veale E, Armstrong J . THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Introduction and Other Protein Targets. Br J Pharmacol. 2019; 176 Suppl 1:S1-S20. PMC: 6844537. DOI: 10.1111/bph.14747. View

14.

Brown K, Poon G, Birkenhead D, Pena O, Falsafi R, Dahlgren C . Host defense peptide LL-37 selectively reduces proinflammatory macrophage responses. J Immunol. 2011; 186(9):5497-505. DOI: 10.4049/jimmunol.1002508. View

15.

Kahlenberg J, Carmona-Rivera C, Smith C, Kaplan M . Neutrophil extracellular trap-associated protein activation of the NLRP3 inflammasome is enhanced in lupus macrophages. J Immunol. 2012; 190(3):1217-26. PMC: 3552129. DOI: 10.4049/jimmunol.1202388. View

16.

Ali A, Townes C, Hall J, Pickard R . Maintaining a sterile urinary tract: the role of antimicrobial peptides. J Urol. 2009; 182(1):21-8. DOI: 10.1016/j.juro.2009.02.124. View

17.

Leemans J, Stokman G, Claessen N, Rouschop K, Teske G, Kirschning C . Renal-associated TLR2 mediates ischemia/reperfusion injury in the kidney. J Clin Invest. 2005; 115(10):2894-903. PMC: 1201659. DOI: 10.1172/JCI22832. View

18.

Chen J, Chen J, Harris R . Deletion of the epidermal growth factor receptor in renal proximal tubule epithelial cells delays recovery from acute kidney injury. Kidney Int. 2012; 82(1):45-52. PMC: 3376190. DOI: 10.1038/ki.2012.43. View

19.

Alexander S, Fabbro D, Kelly E, Mathie A, Peters J, Veale E . THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Catalytic receptors. Br J Pharmacol. 2019; 176 Suppl 1:S247-S296. PMC: 6844576. DOI: 10.1111/bph.14751. View

20.

Chromek M, Slamova Z, Bergman P, Kovacs L, Podracka L, Ehren I . The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection. Nat Med. 2006; 12(6):636-41. DOI: 10.1038/nm1407. View