Sepsis-induced acute kidney injury (AKI) represents a severe medical complication. Recently, there is growing evidence indicating the regulatory role of long non-coding RNAs (lncRNAs) in AKI pathophysiology. The present study investigated lncRNA DLX6 antisense RNA 1 (DLX6-AS1) expression in septic AKI patients and to decipher the relevant mechanisms underlying DLX6-AS1-mediated HK-2 cell pyroptosis in lipopolysaccharide (LPS)-induced AKI. The results revealed that DLX6-AS1 was up-regulated in the serum from septic AKI patients. DLX6-AS1 expression were positively associated with the creatinine levels in the serum from the septic AKI patients. In vitro studies showed that LPS induced cytotoxicity and enhanced DLX6-AS1 expression of HK-2 cells; increased NLR family pyrin domain containing 3 (NLRP3), interleukin (IL)-1β and IL-18 expression. DLX6-AS1 overexpression promoted cytotoxicity and pyroptosis of HK-2 cells; while DLX6-AS1 knockdown counteracted the LPS-induced cytotoxicity and pyroptosis of HK-2 cells. More importantly, DLX6-AS1 sponged miR-223-3p resulting in repression of miR-223-3p expression in HK-2 cells. MiR-223-3p could bind to the 3′ untranslated region of NLRP3, which results in the suppressed NLRP3 expression of HK-2 cells. Further rescue experiments showed that enhanced miR-223-3p expression partially reversed the cytotoxicity and pyroptosis of HK-2 cells upon LPS stimulation or with DLX6-AS1 overexpression. Conclusively, this study identified enhanced DLX6-AS1 expression in the serum from AKI patients. Further mechanistic findings deciphered that DLX6-AS1 mediated LPS-mediated cytotoxicity and pyroptosis in HK-2 via miR-223-3p/NLRP3 axis.

败血症诱发的急性肾损伤（AKI）代表严重的医学并发症。最近，越来越多的证据表明长非编码RNA（lncRNA）在AKI病理生理中的调节作用。本研究调查了败血性AKI患者中lncRNA DLX6反义RNA 1（DLX6-AS1）的表达，并解释了脂多糖（LPS）诱导的AKI中DLX6-AS1介导的HK-2细胞凋亡的相关机制。结果显示败血性AKI患者血清中的DLX6-AS1上调。DLX6-AS1表达与脓毒症AKI患者血清中的肌酐水平呈正相关。体外研究表明，LPS诱导HK-2细胞的细胞毒性并增强DLX6-AS1表达。增加了含有3（NLRP3），白介素（IL）-1β和IL-18表达的NLR家族的吡啶结构域。DLX6-AS1过表达促进HK-2细胞的细胞毒性和细胞凋亡。而DLX6-AS1组合可抵消LPS诱导的HK-2细胞的细胞毒性和细胞凋亡。更重要的是，DLX6-AS1对miR-223-3p进行了海绵化处理，导致HK-2细胞中miR-223-3p的表达受到抑制。MiR-223-3p可以与NLRP3的3'非翻译区结合，从而导致HK-2细胞的NLRP3表达受到抑制。进一步的抢救实验表明，经LPS刺激或DLX6-AS1过表达，增强的miR-223-3p表达可部分逆转HK-2细胞的细胞毒性和细胞凋亡。结论是，这项研究确定了AKI患者血清中DLX6-AS1表达的增强。进一步的机理研究发现，DLX6-AS1通过miR-223-3p / NLRP3轴介导了HK-2中LPS介导的细胞毒性和细胞凋亡。