miR‐542‐5p targets GREM1 to affect the progression of renal fibrosis

• Published in: Journal of biochemical and molecular toxicology Vol. 38; no. 9; pp. e23818 - n/a
• Main Authors: Pang, Shuting, Xie, Boji, Feng, Bingmei, Xu, Guiling, Ye, Qinglin, Chen, Xuesong, Ruan, Liangping, Chen, Hong, Pan, Shang‐Ling, Xue, Chao, Li, Wei
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.09.2024
• Subjects: 3' Untranslated regions; Animals; Binding sites; Cell Line; Chromosome 5; CKD; Data analysis; Datasets; Disease Progression; DNA microarrays; Down-regulation; Epithelium; Fibronectin; Fibrosis; Fibrosis - genetics; Gene expression; Genes; GREM1; Gremlin protein; Growth factors; Humans; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Kidney - metabolism; Kidney - pathology; Kidney diseases; Kidney Diseases - genetics; Kidney Diseases - metabolism; Kidney Diseases - pathology; Kidneys; Male; Mice; Mice, Inbred C57BL; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; miR‐542‐5p; Polycystic kidney; Predictive control; Regulatory mechanisms (biology); renal fibrosis; Reporter gene; TGF‐β1; Therapeutic targets; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Ureteral Obstruction - genetics; Ureteral Obstruction - pathology; GREM1; TGF‐β1; renal fibrosis; CKD; miR‐542‐5p
• ISSN: 1095-6670; 1099-0461; 1099-0461
• DOI: 10.1002/jbt.23818

Renal fibrosis (RF) is a typical pathological presentation of end‐stage chronic kidney disease (CKD) and autosomal dominant polycystic kidney disease (ADPKD). However, the precise regulatory mechanisms governing this re‐expression process remain unclear. Differentially expressed microRNAs (miRNAs) associated with RF were screened by microarray analysis using the Gene Expression Omnibus (GEO) database. The miRNAs upstream of the genes in question were predicted using the miRWalk database. The miRNAs involved in the two GEO data sets were intersected to identify key miRNAs; their regulatory pathways were investigated using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Subsequently, the effects and the underlying mechanisms of target miRNA on RF were examined in a unilateral ureteral obstruction (UUO)‐induced mice renal fibrotic model and a transforming growth factor‐β1 (TGF‐β1)‐induced tubular epithelium (HK‐2) fibrotic cell model. In total, 109 and 32 differentially expressed miRNAs were identified in the GSE133530 and GSE80247 data sets, respectively. GREM1 was identified as a hub gene, where its 2196 upstream miRNAs were predicted; miR‐574‐5p was found to be downregulated and closely related to fibrosis after data set intersection and enrichment analyses, thus was selected for further investigation. A differential expression heatmap (GSE162794) showed that miR‐542‐5p was downregulated. The expression of GREM1 mRNA was upregulated, whereas that of miR‐542‐5p was downregulated in UUO mice and fibrotic HK‐2 cells as compared with the relevant controls. The binding site of miR‐542‐5p was predicted at the 3'UTR region of GREM1 and was confirmed by subsequent dual luciferase reporter gene assay. Western blot analysis showed that Gremlin‐1 and Fibronectin were significantly upregulated after induction of TGF‐β1; when miR‐542‐5p was overexpressed or GREM1 mRNA was interfered, the upregulations of Gremlin‐1 and Fibronectin were significantly reduced. Our research demonstrates that miR‐542‐5p plays a critical role in the progression of RF, and thus may be a promising therapeutic target for CKD and ADPKD. Renal fibrosis (RF) is one part of the progression of chronic kidney disease (CKD). We found that when miR‐542‐5p was overexpressed or GREM1 was interfered, the upregulation of Gremlin‐1 and Fibronectin were reduced. MiR‐542‐5p plays a critical role in the progress of RF and may be a target for CKD.