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  • Fas ligand FasL the natural ligand of Fas can interact

    2022-05-17

    Fas ligand (FasL), the natural ligand of Fas, can interact with Fas and thus induce cell apoptosis through the cascade of death signal in various cell types [8]. Additionally, Fas, which is a member of the tumor necrosis factor (TNF) receptor superfamily and death receptor family, is one kind of transmembrane receptors that widely present in body organs including kidney, heart, liver, brain, lymphoid tissues, liver, and thymus [9]. Moreover, the suppression of Fas/FasL pathway has been demonstrated to have an inhibited effect on RIRI rats [10]. Furthermore, miR-204-5p was presumed to have a binding site on FasL in RNA22 website. It has been revealed that some miRs are key factors for the development and physiological maintenance of kidney, and the renal dysfunction and kidney diseases occurs when the Dicer, a key enzyme for miR production, is ablated [11]. MiR-204-5p, which was previously known as miR-204 [12], has been reported to have suppressed effect on chemokine generation and inflammation in renal tubular epithelial oxedrine via the modulation of interleukin-6/interleukin-6 receptor pathway [13]. Besides, a recent study displayed that miR-204-5p was down-regulated and was essential role for high stage and high grade of clear cell renal cell carcinoma (RCC) [14]. Furthermore, a prior study highlighted the downregulation of miR-204 in renal injury induced by ischemia-reperfusion injury [15]. Based on the aforementioned information, we hypothesized that miR-204-5p and Fas/FasL pathway may be involved in RIRI progression. Therefore, we conducted this study to explore the molecular mechanism involved in miR-204-5p affected the onset and development of RIRI in mice by regulating the Fas/FasL pathway.
    Results
    Discussion RIRI is an inflammatory disease that results from a sudden restriction of blood supply in particular organ, and during this process, the hypoxia and reperfusion can induce a strong inflammation, oxidative stress reaction and functional incapacitation of organs [17]. RIRI is correlated with hospital costs for major cardiac, transplantation, or vascular surgery [18]. Recently, miRs are reported to be implicated in the nosogenesis of RIRI and serve as prognostic biomarkers by regulating related genes [7]. In this study, we aimed to find out the mechanism that miR-204-5p affected RIRI, and we finally found that elevated miR-204-5p could inhibit Fas and FasL expression, thereby further alleviating RIRI progression. Initially, we observed that the Fas and FasL levels elevated significantly in renal tissues of mice with RIRI, and we also found down-regulation of miR-204-5p in RIRI mice. Fas, a receptor also named as CD95, is a member of the TNF family which can activate the alleged death-receptor pathway of apoptosis by interacting with its ligand FasL [19]. A prior study observed the critical role of Fas/FasL pathway played in the nosogenesis of severe ischemic kidney injury through the apoptosis and necrosis of tubule [20]. Besides, Liu et al. reported that the reduction of Fas and FasL expression could mitigate RIRI in rats via the down-regulation of serum Cr and BUN levels [10]. Previous study also showed that the miR-204-5p was poorly expressed in progressive chronic kidney disease, and involved in inflammation, intra-cellular signaling, apoptosis, and cell-cell interaction [21]. Furthermore, X Shu et al. has revealed that the down-regulation of miR-204-5p in clear cell RCC was associated with both tumorigenesis and recurrence [22]. In line with our study, another study also demonstrated that miR-204 was poorly expressed in renal injury induced by ischemia-reperfusion injury [15]. Based on the biological prediction website and the luciferase activity determination, we found that FasL was a putative target of miR-204-5p and was negatively governed by miR-204-5p. Interestingly, Fas/FasL pathway has been reported as a negative target of miR-98 in myocardial cells and a modulator of cell apoptosis, as well as the pathogenesis of myocarditis [23]. Hence, miR-204-5p might alleviate RIRI by inhibiting Fas and FasL.