miR-21 and miR-214 Are Consistently Modulated during Renal Injury in Rodent Models

Denby, Laura; Ramdas, Vasudev; McBride, Martin W.; Wang, Joe; Robinson, Hollie Christine; McClure, John; Crawford, Wendy; Lu, Ruifang; Hillyard, Dianne; Khanin, Raya; Agami, Reuven; Dominiczak, Anna F.; Sharpe, Claire C.; Baker, Andrew H.

doi:10.1016/j.ajpath.2011.04.021

Cited by 101 publications

(103 citation statements)

References 45 publications

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“…39 In agreement with previous reports, we demonstrated that miR-214-3p was regulated by TGF-β1. 21 Here, we established that TGF-β1 induced transcription of pri-miR-199/214 and expression of all 4 mature miRNAs. We identified an increase in expression of the miR-199/214 axis in RV and lung from mice and rats exposed to the SU 4516 hypoxia model of PAH.…”

Section: Discussionmentioning

confidence: 99%

“…13,21,25 In order to assess whether a change in fibrosis was important in the RV phenotype observed, we assessed expression of collagen, type I, alpha 1 (COL1A1) and collagen, type 3, alpha 1 (COL3A1) in male RV. We found no significant change in expression level between groups (Fig.…”

Section: Analysis Of Fibrosis Hypertrophy and Mir-214 Targets In Inmentioning

confidence: 99%

“…21,28,29 Therefore, we investigated expression of the pri-miR-199/214 transcript and mature miRNAs in mouse and rat models of PAH.…”

Section: Mir-214 Is Induced By Tgf-β1 In Pasmcsmentioning

confidence: 99%

“…[21][22][23][24] While in the heart, miR-214 ablation can be protective or deleterious, depending on the injury; in the kidney, miR-214 knockout is protective against fibrosis. 25 TGF-β1 is a critically important mediator of pathophysiological events in PAH and fibrosis.…”

mentioning

confidence: 99%

“…MicroRNA miR-214 is induced by transforming growth factor beta 1 (TGF-β1) 21 and is upregulated in kidney and liver fibrosis. [21][22][23][24] While in the heart, miR-214 ablation can be protective or deleterious, depending on the injury; in the kidney, miR-214 knockout is protective against fibrosis.…”

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confidence: 99%

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Regulation and Function of miR‐214 in Pulmonary Arterial Hypertension

et al. 2016

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Dysregulation of microRNAs (miRNAs) can contribute to the etiology of diseases, including pulmonary arterial hypertension (PAH). Here we investigated a potential role for the miR-214 stem loop miRNA and the closely linked miR-199a miRNAs in PAH. All 4 miRNAs were upregulated in the lung and right ventricle (RV) in mice and rats exposed to the Sugen (SU) 5416 hypoxia model of PAH. Further, expression of the miRNAs was increased in pulmonary artery smooth muscle cells exposed to transforming growth factor β1 but not BMP4. We then examined miR-214 −/− mice exposed to the SU 5416 hypoxia model of PAH or normoxic conditions and littermate controls. There were no changes in RV systolic pressure or remodeling observed between the miR-214 −/− and wild-type hypoxic groups. However, we observed a significant increase in RV hypertrophy (RVH) in hypoxic miR-214 −/− male mice compared with controls. Further, we identified that the validated miR-214 target phosphatase and tensin homolog was upregulated in miR-214 −/− mice. Thus, miR-214 stem loop loss leads to elevated RVH and may contribute to the heart failure associated with PAH. Pulmonary arterial hypertension (PAH) is a disease characterized by narrowing of the small pulmonary arteries, leading to vascular remodeling, an elevation in pulmonary artery pressure, right ventricular hypertrophy (RVH), and heart failure. 1 Current therapies for PAH aim to reverse the endothelial dysfunction and vasoconstriction observed. 2 However, despite these therapies, PAH mortality rates remain high, and the 3-year survival of patients is only 54.9%. 3 Changes in the pulmonary vasculature are the primary cause of PAH; however, right ventricle (RV) function is a major determinant of the severity of symptoms and prognosis of pulmonary hypertension. Many therapies in development for PAH are focused on targeting the RV since heart failure is the ultimate cause of mortality in PAH. 4 PAH is predominant in females, with female ∶ male ratios of 1.4-4.1 ∶ 1. 5 Sexual dimorphism has also been observed in RV failure. Female PAH patients exhibit improved RV ejection fraction and survival compared with men. 6 This could be due at least in part to the protective effect of estrogen on RV function. 7,8 MicroRNAs (miRNAs) are involved in multiple cellular responses during normal development and disease; they act as posttranscriptional regulators to fine-tune protein synthesis. Evidence has emerged for a key role for miRNA in regulation of the cellular processes involved in PAH. We previously demonstrated that a range of miRNAs are dysregulated in rats exposed to models of PAH. 9 Later studies have shown that miR-21, the miR-143/145 cluster, miR-27a, the miR-17-92 cluster, miR-124, miR-150, miR-138, miR-190, miR-204, miR-206, miR-210, and miR-328 play a role in the development of PAH. 10 Multiple miRNAs could potentially be targeted in concert as therapeutics in PAH. 11 MicroRNA miR-214 is transcribed as a bicistronic primary transcript, which is processed to generate 4 separate mature miRNAs...

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Section: Discussionmentioning

confidence: 99%

Section: Analysis Of Fibrosis Hypertrophy and Mir-214 Targets In Inmentioning

confidence: 99%

“…21,28,29 Therefore, we investigated expression of the pri-miR-199/214 transcript and mature miRNAs in mouse and rat models of PAH.…”

Section: Mir-214 Is Induced By Tgf-β1 In Pasmcsmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Regulation and Function of miR‐214 in Pulmonary Arterial Hypertension

et al. 2016

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High glucose increases miR‐214 to power a feedback loop involving PTEN and the Akt/mTORC1 signaling axis

et al. 2019

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The mechanism of PTEN repression by high glucose in diabetic nephropathy is not known. Using proximal tubular cells, we show that inhibition of PI3 kinase/Akt and their inactive enzymes prevents high glucose‐induced PTEN downregulation. Similarly, rapamycin (Rapa) and shRaptor block suppression of PTEN by high glucose. In contrast, the constitutive activation of Akt and mechanistic target of rapamycin (mTOR)C1 decrease the expression of PTEN, similarly to high glucose. Remarkably, PI3 kinase/Akt/mTORC1 inhibition significantly attenuates high glucose‐stimulated increase in miR‐214, which targets PTEN, while constitutively active Akt/mTORC1 increases miR‐214. Furthermore, anti‐miR‐214 and mTORC1 inhibition block high glucose‐induced hypertrophy and fibronectin expression. These results reveal the first evidence for the presence of a high glucose‐forced positive feedback conduit between the three‐layered kinase cascade and miR‐214/ PTEN in tubular cell injury.

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RNA therapeutics: Identification of novel targets leading to drug discovery

Qadir

Bukhat

Rasul

et al. 2019

J of Cellular Biochemistry

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The established concept that RNA works only for protein synthesis has been changed over the past few decades and shifted towards therapeutic purposes. Almost 98% of mammalian genome is transcribed into nonprotein coding RNA termed as noncoding RNA (ncRNA) which plays regulatory role in molecular and cellular functions as controlling gene expression. These ncRNAs are classified as long noncoding RNA (lncRNA), short noncoding RNA (sncRNA), and translational/structural RNA which possess diverse functions. These ncRNAs regulate expression of normal gene and modulate disease development and progression. The characterization of ncRNA genes and their mechanisms can aid in disease diagnosis, examining its development and direct specific therapies in different disease treatments. Due to their unique modes of action, they are designated as novel class of targets leading to drug discovery. The modulation in these ncRNAs can enhance therapeutic treatments against different diseases by targeting mRNA for its cleavage via antisense olionucleotides (ASOs)/DNA duplex, RNA alternative splicing/editing, chromatin modification, transcriptional/translational interference, RNA masking, small interfering RNA/microRNA‐based gene silencing and by inducing immunity via RNA‐based vaccination. Here in this review, we tried to summarize the emerging fields of ncRNA, their role in different diseases, their modes of action, and their potential in target identification and therapeutic drug development.

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miR-21 and miR-214 Are Consistently Modulated during Renal Injury in Rodent Models

Abstract: Transforming growth factor (TGF)-

Cited by 101 publications

References 45 publications

Regulation and Function of miR‐214 in Pulmonary Arterial Hypertension

Regulation and Function of miR‐214 in Pulmonary Arterial Hypertension

High glucose increases miR‐214 to power a feedback loop involving PTEN and the Akt/mTORC1 signaling axis

RNA therapeutics: Identification of novel targets leading to drug discovery

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