MicroRNA-19a Targets Fibroblast Growth Factor-Inducible Molecule 14 and Prevents Tubular Damage in Septic AKI.

Jun Hong,Ren-Hua Sun,Yang Zheng,Xiang-Hong Yang,Bang-Chuan Hu,Shi-Jing Mo,Zi-Qiang Shao,Run Zhang,Liang Xu

doi:10.1155/2020/2894650

Jun Hong, Ren-Hua Sun + Show 7 more

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https://doi.org/10.1155/2020/2894650

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Abstract

Fibroblast growth factor-inducible molecule 14 (Fn14) plays a principal role in triggering tubular damage during septic acute kidney injury (AKI). Here, we explore the mechanism underlying Fn14 deregulation in septic AKI. We identify Fn14 as a bona fide target of miR-19a, which directly binds to 3′ UTR of Fn14 for repression independent of cylindromatosis (CYLD), the deubiquitinase (DUB) downstream of miR-19a, and thereby antagonizes the LPS-induced tubular cell apoptosis. Genetic ablation of Fn14, but not of CYLD, abolishes the ability of miR-19a to antagonize the tubular apoptosis by lipopolysaccharide (LPS). In mice, systemic delivery of miR-19a confers protection against septic AKI. Our findings implicate that miR-19a may serve as a promising therapeutic candidate in the prevention of septic AKI.

Highlights

Septic acute kidney injury (AKI) is the most thorny organ failure (OF) and common cause of mortality in the intensive care unit (ICU), with the simultaneous presence of both sepsis-3.0 and Kidney Disease: Improving Global Outcomes (KDIGO) criteria as the clinical diagnosis [1, 2]
Similar results in both cases were recapitulated in murine macrophage-like RAW 264.7 cells (P < 0:05, Figures 1(b) and 1(c)), indicating that the repressive role of miR-19a in factor-inducible molecule 14 (Fn14) is a common feature not restricted to cell lineage
These findings are in line with a luciferase reporter assay where a luciferase reporter containing the Fn14-3′ UTR with wildtype or mutant miR-19a seed-pairing region was transfected into the mock, negative control- (NC-), or miR-19aexpressed cells, showing that miR-19a, instead of mock or NC, remarkably reduced the activities of the luciferase reporter fused to the wild-type, but not the mutant, Fn14-3′ UTR in all cells tested (P < 0:05 and P < 0:01, Figure 1(d))

Summary

Introduction

Septic acute kidney injury (AKI) is the most thorny organ failure (OF) and common cause of mortality in the intensive care unit (ICU), with the simultaneous presence of both sepsis-3.0 and Kidney Disease: Improving Global Outcomes (KDIGO) criteria as the clinical diagnosis [1, 2]. The main pathological features of septic AKI include deleterious endotoxemia resulting from systemic inflammatory response syndrome (SIRS), abnormal serum creatinine (Scr), and blood urea nitrogen (BUN) levels due to tubular damage. Fn14 is ubiquitously expressed in various tissues and has been reported to participate in multiple physiological and pathological processes including inflammation, ischemia-reperfusion (IR) injury, cell proliferation, differentiation, and apoptosis [4]. Fn14 expression is relatively low in normal healthy tissues, while it could be rapidly activated in response to stress stimuli, which represents one of the main regulatory mechanisms for evoking inflammation or apoptosis. Our previous study demonstrated that lipopolysaccharide (LPS) triggers tubular cell apoptosis as a result of Fn14 stabilization, and blockade of Fn14 is sufficient to improve kidney function and prevent septic AKI in mice [7]. The mechanism underlying Fn14 deregulation in tubular damage during septic AKI remains largely unknown

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