Identification and functional mechanism verification of key microRNAs associated with the fibrosis progression in chronic kidney disease

Abstract

Abstract Background: Chronic kidney disease (CKD) is a serious threat to human health worldwide, and its incidence is increasing annually. The incidence of CKD is a worldwide problem that heavily threatens human health and is increasing annually. A growing amount of information is emerging about the role of miRNAs in the regulation of renal fibrosis, which has aroused interest in the development of drugs that block pathogenic miRNAs or restore protective miRNAs levels. Methods: The aim of this study was to identify the microRNAs (miRNAs) differentially expressed in renal tissues from patients with progressive DN and FSGS of high fibrosis scores to investigate the function and mechanism of miRNAs in renal fibrosis by using kidney tissues from normal and MCD patients as controls. First, we investigated the expression profiles of miRNAs in human kidney biopsy samples using microarray. Then, two new miRNAs were selected to explore the biological functions in TGF-β1 or HG -induced cell models using human proximal renal tubule cells (HK-2). GO and KEGG Pathway Enrichment Analysis were used to explore the target genes and their mechanism in renal fibrosis. Results: The kidney biopsy samples from three types of diseases representing different fibrosis states, two novel miRNAs, hsa-miR-1470-3p and hsa-miR-4483-3p, were detected as consistently differentially expressed among all three types of patient's renal samples and in mice model. In vitro, hsa-miR-4483-3p was suppressed, whereas hsa-miR-1470-3p was induced by treatment with TGF-β1 or HG. Inhibition of hsa-miR-1470-3p or overexpression of hsa-miR-4483-3p promoted HG or TGF-β1-induced fibrosis in HK-2 cells. The further study revealed that MMP-13 and TIMP1 were the target genes of hsa-miR-1470-3p and hsa-miR-4483-3p, respectively. Conclusion: In conclusion, the present study identifies newly dysregulated miRNA profiles related to fibrosis kidneys. Hsa-miR-1470-3p and hsa-miR-4483-3p are demonstrated to involve in kidney fibrosis by regulation of MMP13, TIMP1 respectively. Our results may represent a promising research direction for renal disorders and help identify new biomarkers and therapeutic targets for chronic kidney disease.