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. 2017 Aug 1;313(2):F553-F559.
doi: 10.1152/ajprenal.00493.2016. Epub 2017 May 17.

A Model-Specific Role of microRNA-223 as a Mediator of Kidney Injury During Experimental Sepsis

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Free PMC article

A Model-Specific Role of microRNA-223 as a Mediator of Kidney Injury During Experimental Sepsis

James F Colbert et al. Am J Physiol Renal Physiol. .
Free PMC article

Abstract

Sepsis outcomes are heavily dependent on the development of septic organ injury, but no interventions exist to interrupt or reverse this process. microRNA-223 (miR-223) is known to be involved in both inflammatory gene regulation and host-pathogen interactions key to the pathogenesis of sepsis. The goal of this study was to determine the role of miR-223 as a mediator of septic kidney injury. Using miR-223 knockout mice and multiple models of experimental sepsis, we found that miR-223 differentially influences acute kidney injury (AKI) based on the model used. In the absence of miR-223, mice demonstrated exaggerated AKI in sterile models of sepsis (LPS injection) and attenuated AKI in a live-infection model of sepsis (cecal ligation and puncture). We demonstrated that miR-223 expression is induced in kidney homogenate after cecal ligation and puncture, but not after LPS or fecal slurry injection. We investigated additional potential mechanistic explanations including differences in peritoneal bacterial clearance and host stool virulence. Our findings highlight the complex role of miR-223 in the pathogenesis of septic kidney injury, as well as the importance of differences in experimental sepsis models and their consequent translational applicability.

Keywords: acute kidney injury; microRNA-223; sepsis.

Figures

Fig. 1.
Fig. 1.
Kidney injury is exaggerated in miR-223X-/Y mice after intraperitoneal LPS. A: plasma blood urea nitrogen (BUN). B: kidney homogenate neutrophil gelatinase-associated lipocalin (NGAL) quantified by RT-PCR. C: kidney homogenate kidney injury molecule-1 (KIM-1) quantified by RT-PCR. D: kidney homogenate interleukin-6 (IL-6) quantified by RT-PCR. *P < 0.05 by Student’s 2-tailed t-test, ANOVA. n > 3 replicates per group.
Fig. 2.
Fig. 2.
Kidney injury is attenuated in miR-223X-/Y mice after CLP. A: plasma BUN. B: kidney homogenate NGAL quantified by RT-PCR. C: kidney homogenate KIM-1 quantified by RT-PCR. D: kidney homogenate IL-6 quantified by RT-PCR. *P < 0.05 by Student’s 2-tailed t-test, ANOVA. n > 3 replicates per group.
Fig. 3.
Fig. 3.
Bacterial growth and virulence are not impacted by miR-223. A: peritoneal bacterial growth quantified by peritoneal lavage fluid culture 24 h after CLP. B: representative trypticase soy agar plate demonstrating quantification of peritoneal lavage fluid. C: plasma BUN. D: kidney homogenate NGAL quantified by RT-PCR. n > 3 replicates per group.
Fig. 4.
Fig. 4.
miR-223X-/Y mice do not demonstrate increased renal susceptibility to intraperitoneal MRSA. A: 24-h mortality in wild-type mice after intraperitoneal injection of various doses of MRSA. B: plasma BUN after intraperitoneal injection of 107 CFU of MRSA. *P < 0.05 by Student’s 2-tailed t-test, ANOVA. n > 3 replicates per group.
Fig. 5.
Fig. 5.
miR-223 expression differs based on injury model. Kidney homogenate miR-223 expression quantified by RT-PCR in multiple models of experimental sepsis: intraperitoneal LPS injection (A), CLP (B), and intraperitoneal fecal slurry injection (C). D demonstrates the absence of miR-223 in miR-223X-/Y mouse kidney homogenate. *P < 0.05 by Student’s 2-tailed t-test, ANOVA. n > 3 replicates per group.

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