Noncoding RNAs as therapeutic targets in early stage diabetic kidney disease

Abstract

Diabetic kidney disease (DKD) is a major renal complication of diabetes that leads to renal dysfunction and end-stage renal disease (ESRD). Major features of DKD include accumulation of extracellular matrix proteins and glomerular hypertrophy, especially in early stage. Transforming growth factor-β plays key roles in regulation of profibrotic genes and signal transducers such as Akt kinase and MAPK as well as endoplasmic reticulum stress, oxidant stress, and autophagy related to hypertrophy in diabetes. Many drugs targeting the pathogenic signaling in DKD (mostly through protein-coding genes) are under development. However, because of the limited number of protein-coding genes, noncoding RNAs (ncRNAs) including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are attracting more attention as potential new drug targets for human diseases. Some miRNAs and lncRNAs regulate each other (by hosting, enhancing transcription from the neighbor, hybridizing each other, and changing chromatin modifications) and create circuits and cascades enhancing the pathogenic signaling in DKD. In this short and focused review, the functional significance of ncRNAs (miRNAs and lncRNAs) in the early stages of DKD and their therapeutic potential are discussed.

Bariatric Surgery Alters microRNA Content of Circulating Exosomes in Patients with Obesity

“…Circulating exosomal miRNAs derived from adipocytes may regulate metabolism and mRNA translation in other cells or tissues . Exosomes carrying specific materials are also promising therapeutic tools for the treatment of various diseases . Thus, exosomal miRNAs could be valuable biomarkers for obesity and potential therapeutic targets.…”

Identification of Cooperative Gene Regulation Among Transcription Factors, LncRNAs, and MicroRNAs in Diabetic Nephropathy Progression

“…Diabetes-induced kidney disease is a serious global public health problem, but the molecular mechanism responsible for the pathogenesis of DN from early to late stages remains unclear. The regulatory importance of previously identified TFs, miRNAs, and lncRNAs in the development or progression of DN has been reported (Bernardi et al, 2019;Guo et al, 2019;Sankrityayan et al, 2019), but when several researchers have tried to identify interactions among these factors and the related mechanisms of DN pathogenesis (Kato, 2018), the results have proven inconclusive. Here we provide evidence showing that the combinational performance of TFs, miRNAs, and lncRNAs factors is central to the regulatory mechanisms that control gene expression associated with DN.…”

“…First, it is clear that miRNAs are differentially expressed between healthy control and early and advanced stages of DN. This has led to the postulate that let-7a, miR-21, and miR-29b play important roles in the regulation of DN development and progression (Kato, 2018). Second, actions of ceRNAs represent a novel mechanism of gene regulation that mediates aberrant expression of mRNAs and miRNAs.…”

circRNAs Signature as Potential Diagnostic and Prognostic Biomarker for Diabetes Mellitus and Related Cardiovascular Complications

“…The regulatory roles of ncRNAs in the pathogenesis of DN have received increasing attention. Evidence shows that miRNAs play an important role in the modulation of the renal response to hyperglycemia and the progression of DN [69,70]. However, very little is known about the exact function of circRNAs in the DN condition.…”