lncRNA MALAT1 Promotes Diabetic Nephropathy Progression via miR-15b-5p/TLR4 Signaling Axis

Abstract

Objective. The long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) are closely associated with the pathogenesis of diabetic nephropathy (DN). But a complete mechanism for MALAT1 in DN has yet to be identified. This study investigated the effect of MALAT1 on DN through the regulation of miR-15b-5p/TLR4 signaling. Method. Renal tissues were collected from DN patients. Human renal tubular epithelial cells (HK-2) were used as a model of DN induced by high glucose (HG). We then measured the viability, apoptosis, and inflammatory cytokine levels of HK-2 cells using the corresponding assays. Following transfections of si-MALAT1, si-MALAT1+miR-15b-5p inhibitor, or si-MALAT1+vector TLR4 into HG-stimulated HK-2 cells, cell viability, apoptosis, and inflammatory cytokines were again measured. Furthermore, dual-luciferase reporter assay validated the interactions of MALAT1/miR-15b-5p and miR-15b-5p/TLR4. In addition, the interaction between MALAT1 and miR-15b-5p was investigated by RNA immunoprecipitation (RIP). Results. A significant upregulation of MALAT1 was observed in DN kidney tissues, as well as in HG-stimulated HK-2 cells. MALAT1 knockdown attenuates the inhibition of cell viability, apoptosis, and inflammatory response induced by HG in HK-2 cells. Moreover, a miR-15b-5p inhibitor or TLR4 overexpression reversed the above effects induced by MALAT1 knockdown. Conclusion. These results indicate that reduced MALAT1 ameliorates HG-stimulated HK-2 cell damage through an inhibition of the miR-15b-5p/TLR4 axis. MALAT1 may serve as a biomarker and potential therapeutic target for DN.

The role of long non‐coding RNAs in the development of diabetic kidney disease and the involved clinical application

“…The knockdown of MALAT1-induced reduced HG inhibition of HK-2 cell viability, apoptosis, and inflammatory response was reversed by miR-15b-5p inhibitor or TLR4 overexpression. 105 Additionally, MALAT1 mediated miR-30c/NLRP3, miR-23c/ELAV-like RNA binding protein 1 (ELAVL1), and miR-206 to produce HG-induced HK-2 cell pyroptosis. [106][107][108] Increased secretion of inflammatory factors promotes EMT in renal tubular epithelial cells and peritubular cells and induces tubulointerstitial fibrosis.…”

“…The most extensively researched lncRNA among those linked to DKD renal tubular injury is MALAT1, which primarily functions as a ceRNA for a variety of miRNAs, including miR‐15b‐5p, 105 miR‐30c, 106 miR‐23c, 107 miR‐206 108 , miR‐2355‐3p, 109 miR‐145 110 , and so on. The knockdown of MALAT1‐induced reduced HG inhibition of HK‐2 cell viability, apoptosis, and inflammatory response was reversed by miR‐15b‐5p inhibitor or TLR4 overexpression 105 . Additionally, MALAT1 mediated miR‐30c/NLRP3, miR‐23c/ELAV‐like RNA binding protein 1 (ELAVL1), and miR‐206 to produce HG‐induced HK‐2 cell pyroptosis 106–108 .…”

The regulatory activities of MALAT1 in the development of bone and cartilage diseases

“…In high glucose-treated HK-2 cells, up regulated expression of MALAT1 significantly inhibits cell viability, increases apoptosis, and promotes the productions of IL-1β, IL-6, and TNFα by sponging miR-16b-5p, which targets to degrade TLR4. Knockdown of MALAT1 expression alleviates high glucose-induced injury in HK-2 cells, protecting against diabetic nephropathy ( 31 ). In human liver tissues, the up regulation of MALAT1 expression is associated with the progression of nonalcoholic fatty liver disease (NAFLD).…”

The role of lncRNAs in regulation of DKD and diabetes-related cancer

“…MALAT1 in combination with ACR, α1-MG and creatinine could be helpful for prediction of DKD in DM patients ( 39 ). MALAT1 enhanced diabetic nephropathy via suppression of miR-15b-5p and upregulation of TLR4 signaling ( 40 ).…”