Abstract
Although increasing evidence has confirmed that the apoptosis of renal tubular epithelial cells (RTECs) is a crucial contributor to the onset and development of septic acute kidney injury (AKI), the pathological mechanism by which RTEC apoptosis is upregulated during septic AKI is not entirely clear. In this study, a rat model of septic AKI was induced by a cecal ligation puncture procedure or lipopolysaccharide (LPS) injection. Four differentially expressed long noncoding RNAs (DE-Lncs) in the rat model of septic AKI were determined using RNA-sequencing and verified by qRT-PCR. Among the four DE-Lncs, the expression level of lncRNA NONRATG019935.2 (9935) exhibited the most significant reduction in both septic AKI rats and LPS-treated NRK-52E cells (a rat RTEC line). The overexpression of 9935 suppressed cell apoptosis and p53 protein level in LPS-treated NRK-52E cells, and retarded septic AKI development in the rat model of septic AKI. Mechanistically, 9935 decreased the human antigen R (HuR)-mediated Tp53 mRNA stability by limiting the combination of HuR and the 3′UTR region of Tp53 mRNA in RTECs. The overexpression of HuR abrogated the inhibitory effect of pcDNA-9935 on the LPS-induced apoptosis of NRK-52E and rat primary RTECs. In conclusion, 9935 exerts its role in septic AKI by suppressing the p53-mediated apoptosis of RTECs, and this essential role of 9935 relies on its destructive effect on HuR-mediated Tp53 mRNA stability.
Highlights
Acute kidney injury (AKI) is one of the most common and lifethreatening complications of septic patients
Identification of differentially expressed long noncoding RNAs (DE-Lncs) in cecal ligation puncture (CLP)-engendered AKI A rat model of septic AKI was first constructed through CLP surgery
DISCUSSION an increasing number of researchers have realized that the apoptosis of renal tubular epithelial cells (RTECs) is a crucial contributor to the onset and development of septic AKI [8, 9], the pathological mechanism by which RTEC apoptosis is upregulated during septic AKI is not entirely clear
Summary
Acute kidney injury (AKI) is one of the most common and lifethreatening complications of septic patients. The pathogenesis of septic AKI is traditionally attributed to decreased renal blood flow and acute tubular necrosis [3]. Increasing evidence demonstrates that renal blood flow is normal or even increased in some specific patients and that few septic patients exhibit the features of acute tubular necrosis [4,5,6], suggesting that there must be other mechanisms driving the development of septic AKI. As early as 1999, Hotchkiss et al [7] observed the upregulation of cell apoptosis in patients with sepsis. With the continuous investigation of the pathogenesis of septic AKI, the crucial role of tubular cell apoptosis in septic AKI progression has been widely confirmed
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