lncRNA MALAT1 Promotes Renal Fibrosis in Diabetic Nephropathy by Targeting the miR-2355-3p/IL6ST Axis

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.

Identification of candidate biomarkers and pathways associated with type 1 diabetes mellitus using bioinformatics analysis

“…Genes include STAR (steroidogenic acute regulatory protein) 152 , IL1RN 153 , AQP5 154 , EGR1 155 , SFTPD (surfactant protein D) 156 , KLF10 157 , PODXL (podocalyxin like) 158 , FOXN3 159 , IL6R 160 , PBX1 161 , APOD (apolipoprotein D) 162 , ACVR2B 163 , CD34 164 , INSR (insulin receptor) 165 , APOA5 166 , STAR (steroidogenic acute regulatory protein) 167 , PDK4 168 , GLS (glutaminase) 169 , FKBP5 170 , SLC6A15 171 , MT2A 172 , SLC38A4 173 , AQP7 174 , ABHD15 175 , ABCA1 176 , ZNRF1 177 , PPP1R3B 178 , MAOA (monoamine oxidase A) 179 , UBE2E2 180 , RNASEK (ribonuclease K) 181 , PREX1 182 , DGKG (diacylglycerol kinase gamma) 183 , POSTN (periostin) 184 , COMP (cartilage oligomeric matrix protein) 185 , GAP43 186 , P2RY12 187 , SELL (selectin L) 188 and DLG2 189 were related to type 2 diabetes mellitus. Expression of ERRFI1 190 , ALOX12 191 , SOCS5 192 , DDIT4 193 , DUSP4 194 , IL6ST 195 , DUSP1 196 , SMAD1 197 , NCL (nucleolin) 198 , METTL14 199 , FMOD (fibromodulin) 200 , CYGB (cytoglobin) 201 , UNC5A 202 and TAAR9 203 are believed to be associated with diabetic nephropathy. Genes include FAP (fibroblast activation protein alpha) 204 , EYA4…”

Long Noncoding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 in Extracellular Vesicles Promotes Hepatic Stellate Cell Activation, Liver Fibrosis and β-Catenin Signaling Pathway

“…Growing number of studies have shown that Lnc-MALAT1 is associated with different kind of organ fibrosis ( Leti et al, 2017 ; Liu et al, 2019 ; Huang et al, 2021 ). Choi et al (2010) have reported that downregulation of Lnc-MALAT1 can decrease the level of Rac1 and thus inhibit HSC activation, while other reports indicate that Lnc-MALAT1 is an HSC activator in several animal and in vitro studies ( Dai et al, 2019 ).…”

Identification of candidate biomarkers and pathways associated with type 1 diabetes mellitus using bioinformatics analysis

“…STAR (steroidogenic acute regulatory protein) [153], IL1RN [154], AQP5 [155], EGR1 [156], SFTPD (surfactant protein D) [157], KLF10 [158], PODXL (podocalyxin like) [159], FOXN3 [160], IL6R [161], PBX1 [162], APOD (apolipoprotein D) [163], ACVR2B [164], CD34 [165], INSR (insulin receptor) [166], APOA5 [167], STAR (steroidogenic acute regulatory protein) [168], PDK4 [169], GLS (glutaminase) [170], FKBP5 [171], SLC6A15 [172], MT2A [173], SLC38A4 [174], AQP7 [175], ABHD15 [176], ABCA1 [177], ZNRF1 [178], PPP1R3B [179], MAOA (monoamine oxidase A) [180], UBE2E2 [181], RNASEK (ribonuclease K) [182], PREX1 [183], DGKG (diacylglycerol kinase gamma) [184], POSTN (periostin) [185], COMP (cartilage oligomeric matrix protein) [186], GAP43 [187], P2RY12 [188], SELL (selectin L) [189] and DLG2 [190] have been revealed to be associated with type 2 diabetes mellitus, but these genes might be novel target for T1DM. Expression of ERRFI1 [191], ALOX12 [192], SOCS5 [193], DDIT4 [194], DUSP4 [195], IL6ST [196], DUSP1 [197], SMAD1 [198], NCL (nucleolin) [199], METTL14 [200], FMOD (fibromodulin) [201], CYGB (cytoglobin) [202], UNC5A [203] and TAAR9 [204] are associated with prognosis in patients with diabetic nephropathy, but these genes might be novel target for T1DM. A previous study reported that FAP (fibroblast activation protein alpha) [205], EYA4 [206], BCL9 [207], IRF2BP2 [208], EGR3 [209], GADD45B [210], DMD (dystrophin) [211], LSR (lipolysis stimulated lipoprotein receptor) [212], DLL4 [213], SUN2 [214], SOS1 [215], PIK3CA [216], GAMT (guanidinoacetate N-methyltransferase) [217], RBM47 […”