Abstract
(1) Background: Lipopolysaccharide (LPS)-induced systemic inflammation is associated with septic acute kidney injury (AKI). We investigated the time-dependent miRNA expression changes in the kidney caused by LPS. (2) Methods: Male outbred NMRI mice were injected with LPS and sacrificed at 1.5 and 6 h (40 mg/kg i.p., early phase, EP) or at 24 and 48 h (10 mg/kg i.p., late phase, LP). The miRNA profile was established using miRCURY LNA™ microarray and confirmed with qPCR. Total renal proteome was analyzed by LC-MS/MS (ProteomeXchange: PXD014664). (3) Results: Septic AKI was confirmed by increases in plasma urea concentration and in renal TNF-α and IL-6 mRNA expression. Most miRNAs were altered at 6 and 24 h and declined by 48 h. In EP miR-762 was newly identified and validated and was the most elevated miRNA. The predicted target of miR-762, Ras related GTPase 1B (Sar1b) was downregulated. In LP miR-21a-5p was the most influenced miRNA followed by miR-451a, miR-144-3p, and miR-146a-5p. Among the potential protein targets of the most influenced miRNAs, only aquaporin-1, a target of miR-144-3p was downregulated at 24 h. (4) Conclusion: Besides already known miRNAs, septic AKI upregulated miR-762, which may regulate GTP signaling, and miR-144-3p and downregulated its target, aquaporin-1.
Highlights
The estimated incidence of acute kidney injury (AKI) in hospital admissions is 8–17% [1]
Our MS analysis did not detect any of the so far experimentally validated targets of miR-762, the novel miRNA not associated with septic AKI or renal ischemia before
The miRNome responded to LPS injection mainly by upregulation with only a few downregulated miRNAs, which we could not confirm by qPCR
Summary
The estimated incidence of acute kidney injury (AKI) in hospital admissions is 8–17% [1]. MiR-223 was demonstrated to exaggerate a sterile model of septic AKI (LPS), while it attenuated polymicrobial infection-induced AKI in miR-223 KO mice [10]. The model-specific role of miR-223 can be organ-dependent as myocardial dysfunction and mortality was aggravated in polymicrobial infection in miR-223 KO mice [11] contrary to kidney injury. We evaluated miRNA expression changes in the kidney during LPS-induced AKI. There are several reports on the role of miRNAs in LPS-induced inflammation [12,13,14,15], to our best knowledge, this is the first miRNA microarray investigating the miRNA profile changes in septic AKI.
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