Abstract
Tubular epithelial cells (TECs) represent the primary site of renal ischemia/reperfusion injury (RIRI). However, whether the damage of TECs could drive the initiation of inflammation was unclear. Here we investigated the role of the TECs and macrophages during RIRI. Increased expression of inflammation response and activated M1 macrophage were determined in the mice model of RIRI. Moreover, we demonstrated global miRNA expression profiling of renal exosomes, and miR-374b-5p was most upregulated in these exosomes in vivo. Inhibition of miR-374b-5p in the mice upon RIR operation would alleviate the kidney injury via decreasing the production of proinflammatory cytokines and suppressing the macrophage activation. Similar results were also identified in the hypoxia-induced cell model where exosomal miR-374b-5p was dramatically upregulated. Uptake of exosomes derived from the hypoxic TECs by macrophages would trigger M1 polarization via transferring miR-374b-5p. Besides, we confirmed that miR-374b-5p could directly bind to Socs1 using a dual-luciferase reporter assay. Notably, when we injected the miR-374b-5p-enriched exosomes into mice, a high-level inflammatory response and M1 macrophage activation were performed. Our studies demonstrated that exosomal miR-374b-5p played an essential role in the communication between injured TECs and macrophages, resulting in the M1 macrophage activation during RIRI. The blockage of the release of such exosomes may serve as a new therapeutic strategy for RIRI.
Highlights
Ischemia and subsequent reperfusion injury usually occur when the blood flow is blocked during surgeries or severe diseases
M1 Macrophage Was Activated in the Renal Ischemia/Reperfusion-Induced acute kidney injury (AKI) Model
We observed a higher level of serum creatinine (SCr) and blood urea nitrogen (BUN) in the mice subjected to bilateral RIR operation on day 1, whereas it was decreased on day 3 (Figure 1A)
Summary
Ischemia and subsequent reperfusion injury usually occur when the blood flow is blocked during surgeries or severe diseases. Cardiac dysregulations and surgical interventions, such as kidney transplantation or nephron-sparing surgery, are the leading causes of RIRI (Venkatachalam et al, 2015; Skube et al, 2018) This lesion results in AKI and presents the MicroRNA-374b-5p Worsens Renal Ischemia fundamental problems and even contributes to a high morbidity and mortality rate (Chawla et al, 2014). The hypoxic TECs can facilitate the inflammation response by producing many inflammatory mediators such as MCP-1, TNF-α, and IL-1β, acting as driving factors in kidney diseases (Meldrum et al, 2003; Siegel and Shah, 2003; Lv et al, 2018; Wong et al, 2018). The mechanism of how the TECs transfect these inflammatory signals into macrophage during RIRI still needs to be revealed
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