MicroRNAs in Diabetic Nephropathy: From Biomarkers to Therapy

Simpson, Keith; Wonnacott, Alexa; Fraser, Donald; Bowen, Timothy

doi:10.1007/s11892-016-0724-8

Cited by 124 publications

(106 citation statements)

References 57 publications

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“…From the vast amount of published reports on miRNAs, we now know that they are important regulators of many diverse cellular processes such as pluripotency control, differentiation, proliferation, metabolism, and apoptosis, for example (128). In many disease scenarios, miRNAs have been analyzed as potential biomarkers (129–132), and their small size renders them attractive therapeutic targets. A recent search for “microRNAs” on the clinical trials website, https://clinicaltrials.gov/, shows a number of studies (including active, recruiting, and completed) to determine miRNA expression profiling in blood, serum, or other tissues from patients with a wide range of diseases including various cancers, pathological conditions of the lung, heart, or nervous system, diabetes, and musculoskeletal diseases.…”

Section: Micrornas Regulated By Inflammatory Mediators In Cartilage Amentioning

confidence: 99%

Inflammation and epigenetic regulation in osteoarthritis

Shen

Abu‐Amer

O’Keefe

et al. 2016

Connective Tissue Research

194

140

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Osteoarthritis (OA) was once defined as a non-inflammatory arthropathy, but it is now well-recognized that there is a major inflammatory component to this disease. In addition to synovial cells, articular chondrocytes and other cells of diarthrodial joints are also known to express inflammatory mediators. It has been proposed that targeting inflammation pathways could be a promising strategy to treat OA. There have been many reports of cross-talk between inflammation and epigenetic factors in cartilage. Specifically, inflammatory mediators have been shown to regulate levels of enzymes that catalyze changes in DNA methylation and histone structure, as well as alter levels of non-coding RNAs. In addition, expression levels of a number of these epigenetic factors have been shown to be altered in OA, thereby suggesting potential interplay between inflammation and epigenetics in this disease. This review provides information on inflammatory pathways in arthritis and summarizes published research on how epigenetic regulators are affected by inflammation in chondrocytes. Furthermore, we discuss data showing how altered expression of some of these epigenetic factors can induce either catabolic or anti-catabolic effects in response to inflammatory signals. A better understanding of how inflammation affects epigenetic factors in OA may provide us with novel therapeutic strategies to treat this condition.

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Section: Micrornas Regulated By Inflammatory Mediators In Cartilage Amentioning

confidence: 99%

Inflammation and epigenetic regulation in osteoarthritis

Shen

Abu‐Amer

O’Keefe

et al. 2016

Connective Tissue Research

194

140

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“…[1] Tubular injury plays a critical role in DKD progression, which correlates with renal functional deterioration, a primary change associated with the disease. [2] The pathogenesis of DKD is not clear, but mitochondrial abnormalities largely contribute to its development.…”

Section: Introductionmentioning

confidence: 99%

The mitochondria-targeted antioxidant MitoQ ameliorated tubular injury mediated by mitophagy in diabetic kidney disease via Nrf2/PINK1

et al. 2017

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Mitochondria play a crucial role in tubular injury in diabetic kidney disease (DKD). MitoQ is a mitochondria-targeted antioxidant that exerts protective effects in diabetic mice, but the mechanism underlying these effects is not clear. We demonstrated that mitochondrial abnormalities, such as defective mitophagy, mitochondrial reactive oxygen species (ROS) overexpression and mitochondrial fragmentation, occurred in the tubular cells of db/db mice, accompanied by reduced PINK and Parkin expression and increased apoptosis. These changes were partially reversed following an intraperitoneal injection of mitoQ. High glucose (HG) also induces deficient mitophagy, mitochondrial dysfunction and apoptosis in HK-2 cells, changes that were reversed by mitoQ. Moreover, mitoQ restored the expression, activity and translocation of HG-induced NF-E2-related factor 2 (Nrf2) and inhibited the expression of Kelch-like ECH-associated protein (Keap1), as well as the interaction between Nrf2 and Keap1. The reduced PINK and Parkin expression noted in HK-2 cells subjected to HG exposure was partially restored by mitoQ. This effect was abolished by Nrf2 siRNA and augmented by Keap1 siRNA. Transfection with Nrf2 siRNA or PINK siRNA in HK-2 cells exposed to HG conditions partially blocked the effects of mitoQ on mitophagy and tubular damage. These results suggest that mitoQ exerts beneficial effects on tubular injury in DKD via mitophagy and that mitochondrial quality control is mediated by Nrf2/PINK.

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“…miRNAs have been shown to play important roles in modulating gene expression and regulating diverse biologic processes89. Moreover, evidence shows that miRNAs regulate the expression of key genes associated with kidney diseases and several miRNAs1011121314151617. These miRNAs were shown to regulate fibrotic gene expression and glomerular hypertrophy via targeting transforming growth factor (TGF)-β signaling, high glucose (HG) effects and downstream transcription regulators, or extracellular matrix genes.…”

mentioning

confidence: 99%

Inhibition of the processing of miR-25 by HIPK2-Phosphorylated-MeCP2 induces NOX4 in early diabetic nephropathy

Kato

Deshpande

et al. 2016

Sci Rep

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Phosphorylated methyl-CpG binding protein2 (p-MeCP2) suppresses the processing of several microRNAs (miRNAs). Homeo-domain interacting protein kinase2 (HIPK2) phosphorylates MeCP2, a known transcriptional repressor. However, it is not known if MeCP2 and HIPK2 are involved in processing of miRNAs implicated in diabetic nephropathy. p-MeCP2 and HIPK2 levels were significantly increased, but Seven in Absentia Homolog1 (SIAH1), which mediates proteasomal degradation of HIPK2, was decreased in the glomeruli of streptozotocin injected diabetic mice. Among several miRNAs, miR-25 and its precursor were significantly decreased in diabetic mice, whereas primary miR-25 levels were significantly increased. NADPH oxidase4 (NOX4), a target of miR-25, was significantly increased in diabetic mice. Protein levels of p-MeCP2, HIPK2, and NOX4 were increased in high glucose (HG)- or TGF-β-treated mouse glomerular mesangial cells (MMCs). miR-25 (primary, precursor, and mature) and mRNA levels of genes indicated in the in vivo study showed similar trends of regulation in MMCs treated with HG or TGF-β. The HG- or TGF-β-induced upregulation of p-MeCP2, NOX4 and primary miR-25, but downregulation of precursor and mature miR-25, were attenuated by Hipk2 siRNA. These results demonstrate a novel role for the SIAH1/HIPK2/MeCP2 axis in suppressing miR-25 processing and thereby upregulating NOX4 in early diabetic nephropathy.

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MicroRNAs in Diabetic Nephropathy: From Biomarkers to Therapy

Cited by 124 publications

References 57 publications

Inflammation and epigenetic regulation in osteoarthritis

Inflammation and epigenetic regulation in osteoarthritis

The mitochondria-targeted antioxidant MitoQ ameliorated tubular injury mediated by mitophagy in diabetic kidney disease via Nrf2/PINK1

Inhibition of the processing of miR-25 by HIPK2-Phosphorylated-MeCP2 induces NOX4 in early diabetic nephropathy

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