Resveratrol alleviates sepsis-induced acute kidney injury by deactivating the lncRNA MALAT1/MiR-205 axis.

INTRODUCTION: Resveratrol plays a protective role against sepsis development, and the long noncoding RNA (lncRNA) MALAT1 is an inflammation-relevant biomarker. This investigation attempted to reveal whether resveratrol attenuated inflammation of sepsis-induced acute kidney injury (AKI) by regulating MALAT1. MATERIAL AND METHODS: In total 120 rats were divided into a control group (n = 20), a Sham group (n = 20), a sepsis group (n = 40) and a resveratrol group (n = 40), and serum levels of inflammatory cytokines and AKI biomarkers were determined. An equal number of rats under identical treatments were, additionally, tracked for their survival, and the serum level of lncRNA MALAT1 was measured by RT-PCR. Moreover, septic cell models were constructed by treating HK-2 cells with lipopolysaccharide (LPS), and tumor necrosis factor α (TNF-α), interleukin (IL)-1ß, IL-6 levels released by the cells were determined with ELISA. RESULTS: Resveratrol treatment significantly brought down serum levels of inflammatory cytokines (i.e. TNF-α, IL-1ß and IL-6), kidney function indicators (i.e. Scr, blood urea nitrogen [BUN] and Scys C), AKI biomarkers (i.e. NGAL and KIM-1) and MALAT1 in cecal ligation and puncture (CLP)-induced septic model rats (all p < 0.05), and the life span of septic rats was elongated by resveratrol treatment (p < 0.05). Viability and cytokine release of LPS-treated HK2 cells were rescued by resveratrol (p < 0.05), which was accompanied by a marked fall of MALAT1 expression (p < 0.05). In addition, si-MALAT1 diminished viability and suppressed cytokine release of HK2 cells, while pcDNA3.1-MALAT1 hindered the impact of resveratrol on the inflammatory response of HK2 cells (p < 0.05). Ultimately, miR-205, a protective molecule in sepsis-relevant AKI, was down-regulated by resveratrol and si-MALAT1 (p < 0.05). CONCLUSIONS: Resveratrol relieved sepsis-induced AKI by restraining the lncRNA MALAT1/miR-205 axis.

Downregulation of miR-527 alleviates sepsis-induced acute kidney injury via targeting Beclin1.

BACKGROUND: Sepsis-induced acute kidney injury (AKI) is known to result from the inflammatory responses. MiRNAs participate in the development of sepsis-induced AKI. Nevertheless, the function of miR-527 in sepsis-induced AKI remains unclear. METHODS: Cell viability was evaluated by CCK8 assay, and TUNEL staining was applied to assess cell apoptosis. Pro-inflammatory cytokine (TNF-α, IL-6 and IL-1ß) levels were evaluated by ELISA. Meanwhile, the relation among miR-527 and Beclin1 was detected by dual luciferase report assay. Western blot and RT-qPCR were used to examine the protein and mRNA levels, respectively. Furthermore, an in vivo model was constructed to assess the function of miR-527 in sepsis-induced AKI. RESULTS: MiR-527 downregulation significantly alleviated the symptoms of sepsis-induced AKI in mice. MiR-527 level in HK-2 cells was significantly upregulated by LPS, and downregulation of miR-527 notably reversed LPS-induced inhibition of HK-2 cell viability by inhibiting apoptosis. In addition, LPS greatly increased TNF-α, IL-6 and IL-1ß levels in supernatant of HK-2 cells, while miR-527 inhibitor partially restored this phenomenon. Meanwhile, Beclin1 was found to be the downstream mRNA of miR-527, and miR-527 inhibitor notably upregulated the level of LC3. MiR-527 downregulation reversed LPS-induced HK-2 cell injury through suppression of TGF-ß pathway. CONCLUSION: Downregulation of miR-527 alleviated sepsis-induced AKI via targeting Beclin1. Thus, miR-527 might act as a vital mediator in sepsis-induced AKI.

EZH2 inhibitor GSK343 inhibits sepsis-induced intestinal disorders.

Enhancer of zeste homolog 2 (EZH2) is positively associated with poor clinical outcomes in a number of aggressive tumors. Recent studies have demonstrated that inhibition of EZH2 also suppressed the inflammatory response during sepsis. The present study aimed to investigate whether an inhibitor of EZH2, GSK343, could protect the intestine against sepsis-induced injury in vivo. Mice underwent cecal ligation and perforation (CLP) to induce sepsis and were assigned into three groups: Sham, CLP and CLP + GSK343. For GSK343 treatment, the septic mice were intravenously injected with GSK343 at 6 h post-CLP. The results indicated that EZH2 was highly expressed while tight junction (TJ) proteins ZO-1, occludin and claudin-1 expression was reduced in the intestinal tissue of mice subjected to CLP compared with the sham group. CLP operation also caused intestinal pathological injury and the production of inflammatory cytokines including TNF-α, IL-1ß and IL-6 in both serum and intestinal tissues. Meanwhile, CLP induced cell apoptosis of intestinal tissue based on the increased number of apoptotic cells, reduced expression of Bcl-2 and higher expression of caspase-3 and Bax. However, the presence of GSK343 partially rescued intestinal pathological injury, reduced the level of inflammatory cytokines, repressed cell apoptosis and promoted TJ protein expression. Finally, the decreased number of Paneth cells caused by CLP operation was reversed by GSK343 treatment. In conclusion, the results of the present study demonstrated that GSK343 could protect the intestine against sepsis-induced injury in vivo. Inhibition of EZH2 may provide a therapeutic approach for intestinal dysfunction during sepsis.