Abstract
The mechanism underlying sepsis-associated acute kidney injury (SAKI), which is an independent risk factor for sepsis-associated death, is unclear. A previous study indicates that during sepsis miR-21a-3p accumulates in renal tubular epithelial cells (TECs) as the mediator of inflammation and mediates TEC malfunction by manipulating its metabolism. However, the specific mechanism responsible for the accumulation of miR-21a-3p in TECs during sepsis is unrevealed. In this study, a cecal ligation and puncture- (CLP-) induced sepsis rat model and rat TEC line were used to elucidate the mechanism. Firstly, miR-21a-3p and Ago2 levels were found out to increase in both plasma and TECs during sepsis, and the increase of intracellular Ago2 and miR-21a-3p could be mitigated when Ago2 was either inactivated or downregulated in septic plasma. Moreover, membrane Nrp-1 expression of TECs was increased significantly during sepsis and Nrp-1 knockdown also mitigated the rise of both the intracellular Ago2 and miR-21a-3p levels in TECs incubated with septic plasma. Furthermore, it was revealed that Ago2 can be internalized by TECs mediated with Nrp-1 and this process had no effect on the intracellular content of miR-21a-3p. Both Ago2 and miR-21a-3p could bind to TECs derived Nrp-1 directly. Finally, it was determined that miR-21a-3p was internalized by TECs via Nrp-1 and Ago2 facilitated this process. Taken together, it can be concluded from our results that Ago2 binding miR-21a-3p from septic plasma can be actively internalized by TECs via Nrp-1 mediated cell internalization, and this mechanism is crucial for the rise of intracellular miR-21a-3p content of TECs during sepsis. These findings will improve our understanding of the mechanisms underlying SAKI and aid in developing novel therapeutic strategies.
Highlights
Dysregulated host response to infection results in the development of sepsis, which is the leading cause of death in the intensive care unit (ICU) worldwide [1]
To identify whether miR21a-3p increased in both plasma and tubular epithelial cells (TECs), the cecal ligation and puncture (CLP) sepsis rat model was used in the present study
Because it was well studied that sepsis was induced 12 h after CLP in rats in our former studies [19], the present results indicated that the miR-21a-3p levels in both plasma and TECs were increased significantly during sepsis
Summary
Dysregulated host response to infection results in the development of sepsis, which is the leading cause of death in the intensive care unit (ICU) worldwide [1]. A new definition which was named sepsis 3.0 was developed in 2016 to further refine this complicated process, with an increased focus on early recognizing and treating organ dysfunction in the context of infection to receive better prognosis [3, 4]. Sepsis in patients with pathological conditions, such as chronic obstructive pulmonary disease and coronavirus disease 2019-related pneumonia can exacerbate the disease severity and increase mortality [5,6,7]. MODS, especially acute kidney injury, induced by sepsis, is the independent risk factor of septic death which related mechanisms remain unclear [8, BioMed Research International
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