Non-Coding RNAs as Biomarkers and Therapeutic Targets for Diabetic Kidney Disease

Abstract

Diabetic kidney disease (DKD) is the most common diabetic complication and is a leading cause of end-stage kidney disease. Increasing evidence shows that DKD is regulated not only by many classical signaling pathways but also by epigenetic mechanisms involving chromatin histone modifications, DNA methylation, and non-coding RNA (ncRNAs). In this review, we focus on our current understanding of the role and mechanisms of ncRNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in the pathogenesis of DKD. Of them, the regulatory role of TGF-β/Smad3-dependent miRNAs and lncRNAs in DKD is highlighted. Importantly, miRNAs and lncRNAs as biomarkers and therapeutic targets for DKD are also described, and the perspective of ncRNAs as a novel therapeutic approach for combating diabetic nephropathy is also discussed.

TGF-β Signaling: From Tissue Fibrosis to Tumor Microenvironment

“…In addition, a novel Smad3-dependent long non-coding RNA Erbb4-IR showed various actions in prostate and esophageal squamous cell carcinoma, where one of the actions is to inhibit apoptosis by downregulating tumor suppressor miRNA-145, thus promoting cancer cell proliferation [ 68 , 144 ]. Upregulation of TGF-β/Smad-mediated Erbb4-IR and LRNA9884 were observed in renal fibrosis, as they up-regulate the pathogenic effectors via transcriptional regulation at genomic level [ 145 , 146 , 147 , 148 ]. The pathogenic roles of inflammatory cells in the TGF-β-mediated tissue fibrosis have been intensively elucidated especially on the innate immunity, e.g., macrophage, neutrophil, etc.…”

Interactions among Long Non-Coding RNAs and microRNAs Influence Disease Phenotype in Diabetes and Diabetic Kidney Disease

“…Available evidence has indicated the important roles of lncRNAs in the pathophysiology of diabetic kidney disease (DKD), and the crosstalk between lncRNAs and DKD were reported in recent years [15][16][17][18][19]. Altered expression levels of lncRNAs play key roles in the development of proteinuria and associated diabetic nephropathy (DN) [15,20].…”

“…Available evidence has indicated the important roles of lncRNAs in the pathophysiology of diabetic kidney disease (DKD), and the crosstalk between lncRNAs and DKD were reported in recent years [15][16][17][18][19]. Altered expression levels of lncRNAs play key roles in the development of proteinuria and associated diabetic nephropathy (DN) [15,20]. LncRNAs are involved in the progression of kidney disease through regulation of many important factors, such as pathologic processes in mesangial cells, podocytes, reactive oxidative species, epithelial-to-mesenchymal transition (EMT), endothelial-to-mesenchymal transitions (EndMT) and actions on microRNAs [21][22][23].…”

Transforming Growth Factor-β and Long Non-coding RNA in Renal Inflammation and Fibrosis

“…As previously mentioned, the group of lncRNAs identified in kidneys is highly specific to cell type or disease state. Studies carried out over these years have identified a group of anti- or pro-fibrotic and inflammatory lncRNAs in diabetic, acute and chronic renal diseases ( Tang et al, 2017 , 2018a ; Ren et al, 2019 ; Gu et al, 2020c ) ( Table 1 ).…”