MicroRNAs in kidney fibrosis and diabetic nephropathy: roles on EMT and EndMT

Abstract

MicroRNAs (miRNAs) are a family of small, noncoding RNAs that regulate gene expression in diverse biological and pathological processes, including cell proliferation, differentiation, apoptosis, and carcinogenesis. As a result, miRNAs emerged as major area of biomedical research with relevance to kidney fibrosis. Fibrosis is characterized by the excess deposition of extracellular matrix (ECM) components, which is the end result of an imbalance of metabolism of the ECM molecule. Recent evidence suggests that miRNAs participate in the fibrotic process in a number of organs including the heart, kidney, liver, and lung. Epithelial mesenchymal transition (EMT) and endothelial mesenchymal transition (EndMT) programs play vital roles in the development of fibrosis in the kidney. A growing number of the extracellular and intracellular molecules that control EMT and EndMT have been identified and could be exploited in developing therapeutics for fibrosis. This review highlights recent advances on the role of miRNAs in the kidney diseases; diabetic nephropathy especially focused on EMT and EndMT program responsible for the development of kidney fibrosis. These miRNAs can be utilized as a potential novel drug target for the studying of underlying mechanism and treatment of kidney fibrosis.

Figure 1

Schematic presentation of biogenesis and action of miRNAs. Ago: Argonaute; DGCR8: DiGeorge syndrome critical region 8; elF4E: eukaryotic initiation factor 4E; GW182: glycine-tryptophan protein-182; nt: nucleotides; RISC: miRNA-induced silencing complex; TARBP: transactivation-responsive RNA-binding protein.

Figure 2

Biochemical changes during EMT in fibrosis. Repression of the transcription factors Snail1, Snail2, Zeb1, and Zeb2 is important for the maintenance of epithelial morphology. Several factors that are upregulated in the context of inflammation, including nuclear factor-κB (NF-κB), TGF-β1, bone morphogenetic proteins (BMPs), Wnt, and Notch signaling proteins, can activate the Snail-Zeb pathway, leading to mesenchymal differentiation in these cells. FSP-1: fibroblast-specific protein-1.

Figure 3

Biochemical changes during EndMT program. The EndMT program causes decreased expression of endothelial markers VE-cadherin, CD31, cytokeratins, and type 4 collagen and a gain of mesenchymal markers FSP-1, αSMA, N-cadherin, vimentin, fibronectin, type I and type III collagen, and MMP-2 and MMP-9. FSP-1: fibroblast-specific protein-1; α-SMA: α-smooth muscle actin; and MMP: matrix metalloproteinase.

Figure 4

Implications of miRNAs in renal fibrosis.