Huang Haozi, Zhang Guowei, Ge Zhenying
Department of Endocrinology, Huaihe Hospital of Henan University, Kaifeng, China.
Intensive Care Unit, Adult Cardiovascular Surgery, Fuwai Central China Cardiovascular Hospital, Zhengzhou, China.
Front Pharmacol. 2021 Apr 29;12:647650. doi: 10.3389/fphar.2021.647650. eCollection 2021.
Long noncoding RNA (lncRNAs) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been reported in diabetic nephropathy (DN) about its effect on podocyte function and cell heat shock induced by hyperglycemia. However, the biological mechanism of MALAT1 regulating DN fibrosis needs further study. In this study, SD rats were administrated with streptozotocin (STZ) to establish a diabetes model. , human renal tubular epithelial cells (HK-2 and 293T) were treated with high glucose (HG). Here, we found that MALAT1 was upregulated in renal tissues of diabetic rats and HG-treated cells, and HG treatment promoted cell proliferation and invasion. MALAT1 overexpression aggravated protein levels of collagen I (col I), collagen IV (col IV), fibronectin (FN), and laminin (LN) in HK-2 cells, while MALAT1 knockdown exerted the opposite effect. Moreover, the luciferase reporter gene and pull-down assays demonstrated that MALAT1 interacted with miR-2355-3p. The miR-2355-3p level was downregulated in diabetic rats and HG-treated cells, and MALAT1 overexpression inhibited the miR-2355-3p level. Bioinformatics prediction and luciferase reporter gene assay revealed that interleukin 6 signal transducer (IL6ST) was a target of miR-2355-3p. In addition, miR-2355-3p overexpression attenuated fibrosis-related gene levels in HG-treated cells by inhibiting IL6ST expression and inactivating the recombinant signal transducer and activator of the transcription 3 (STAT3) signaling pathway. Knockdown of miR-2355-3p reversed the inhibitory effect of MALAT1 knockdown on IL6ST, col I, col IV, FN, and LN protein levels in HG-induced cells. Overexpression of MALAT1 aggravated cell damage in HG-induced cells the miR-2355-3p/IL6ST/STAT3 signaling pathway. Finally, enhanced renal fibrosis and kidney tissue damage were observed in diabetic rats. In conclusion, MALAT1 overexpression may enhance renal fibrosis in diabetic rats and cell damage in HG-induced HK-2 cells the miR-2355-3p/IL6ST axis, which provides a new perspective of DN treatment.
长链非编码RNA（lncRNAs）转移相关肺腺癌转录本1（MALAT1）在糖尿病肾病（DN）中对足细胞功能和高血糖诱导的细胞热休克的影响已有报道。然而，MALAT1调节DN纤维化的生物学机制仍需进一步研究。在本研究中，给SD大鼠注射链脲佐菌素（STZ）以建立糖尿病模型。此外，用人肾小管上皮细胞（HK - 2和293T）进行高糖（HG）处理。在此，我们发现MALAT1在糖尿病大鼠的肾组织和HG处理的细胞中上调，并且HG处理促进细胞增殖和侵袭。MALAT1过表达加重了HK - 2细胞中I型胶原（col I）、IV型胶原（col IV）、纤连蛋白（FN）和层粘连蛋白（LN）的蛋白水平，而MALAT1敲低则产生相反的效果。此外，荧光素酶报告基因和下拉实验表明MALAT1与miR - 2355 - 3p相互作用。miR - 2355 - 3p水平在糖尿病大鼠和HG处理的细胞中下调，并且MALAT1过表达抑制miR - 2355 - 3p水平。生物信息学预测和荧光素酶报告基因检测显示白细胞介素6信号转导子（IL6ST）是miR - 2355 - 3p的靶标。此外，miR - 2355 - 3p过表达通过抑制IL6ST表达和使重组信号转导子和转录激活因子3（STAT3）信号通路失活，减轻了HG处理细胞中纤维化相关基因的水平。敲低miR - 2355 - 3p逆转了MALAT1敲低对HG诱导细胞中IL6ST、col I、col IV、FN和LN蛋白水平的抑制作用。MALAT1过表达加重了HG诱导细胞中的细胞损伤，通过miR - 2355 - 3p/IL6ST/STAT3信号通路。最后，在糖尿病大鼠中观察到肾纤维化和肾组织损伤增强。总之，MALAT1过表达可能通过miR - 2355 - 3p/IL6ST轴增强糖尿病大鼠的肾纤维化和HG诱导的HK - 2细胞损伤，这为DN治疗提供了新的视角。
