Cathelicidin-related antimicrobial peptide protects against ischaemia reperfusion-induced acute kidney injury in mice.
Pan. Li-Long LL; Liang. Wenjie W; Ren. Zhengnan Z; Li. Chunqing C; Chen. Yong Y; Niu. Wenying W; Fang. Xin X; Liu. Yanyan Y; Zhang. Ming M; Diana. Julien J; Agerberth. Birgitta B; Sun. Jia J
Key Findings
- LL-37/CRAMP levels drop during acute kidney injury in both humans and mice.
- Mice lacking CRAMP suffer worse kidney damage, more inflammation, and higher NLRP3 activity.
- Giving CRAMP (5 mg/kg IP) before injury cuts kidney damage, inflammation, and NLRP3 activation, and this effect depends on the EGF receptor.
Practical Outcomes
- For now, the work is pre‑clinical, so there’s no ready‑to‑use protocol for biohackers. It does suggest that boosting LL‑37 or targeting the NLRP3 pathway could become a future strategy for kidney protection, but safe dosing, delivery method, and human trials are still needed.
Summary
In mice, giving the natural peptide LL-37 (called CRAMP in mice) before a kidney injury caused by loss of blood flow helped protect the kidneys. It reduced inflammation, cell death, and a specific immune alarm system called NLRP3, and it needed the EGF receptor to work. Humans with acute kidney injury had lower LL-37 levels, hinting the peptide might matter in people too.
Abstract
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. 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<sup>-/-</sup> ) mice by ischaemia/reperfusion (I/R). Therapeutic evaluation of CRAMP was performed with exogenous CRAMP (5 mg·kg<sup>-1</sup> , i.p.) treatment. Cathelicidin expression was inversely related to clinical signs in patients and down-regulated in renal I/R-induced injury in mice. Cnlp<sup>-/-</sup> mice exhibited exacerbated I/R-induced renal dysfunction, aggravated inflammatory responses and apoptosis. Moreover, over-activation of the NLRP3 inflammasome in Cnlp<sup>-/-</sup> 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<sup>-/-</sup> 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. Our results suggest that CRAMP acts as a novel immunomodulatory mediator of AKI and modulation of CRAMP may represent a potential therapeutic strategy.
Study Information
pubmed
2020
2020-02-12T00:00:00.000Z
10.1111/bph.14998
33
64