Abstract
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. In vitro, 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 via 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 via the miR-2355-3p/IL6ST axis, which provides a new perspective of DN treatment.
Highlights
Diabetic nephropathy (DN), one of the most important complications of diabetic patients, is the main cause of death
We demonstrated that the metastasis–associated lung adenocarcinoma transcript 1 (MALAT1) level was upregulated in a time-dependent manner in high glucose (HG)-treated HK-2 and 293T cells (Figures 1F,G)
Our results determined that Long noncoding RNAs (lncRNAs) MALAT1 was upregulated in HK-2 or 293T cell lines, and knockdown of MALAT1 inhibited HG-treated cell damage in HK-2 cells
Summary
Diabetic nephropathy (DN), one of the most important complications of diabetic patients, is the main cause of death. DN has become one of the most lncRNA-MALAT1 Contributes to Diabetic Nephropathy common complications in diabetic patients (Doi et al, 2008; Kanasaki et al, 2013; Thomas and Karalliedde, 2019). Dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium glucose cotransporter-2 (SGLT-2) inhibitors, oral drugs for the treatment of patients with type 2 diabetes mellitus (T2D), are mainly used to control blood glucose (Shimizu et al, 2019). Both of them play a protective role in the progression of renal disease and play an anti-fibrosis role in DN (Gupta and Sen, 2019). It is urgent to find new targets for DN treatment
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