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      Disruption of a miR-29 binding site leading toCOL4A1upregulation causes pontine autosomal dominant microangiopathy with leukoencephalopathy : COL4A1Upregulation in PADMAL

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          Abstract

          Cerebral small vessel disease (cSVD) is a heterogeneous group of disorders. Screening of known cSVD genes identifies the causative mutation in <15% of familial cSVD cases. We sought to identify novel causes of cSVD.

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          Most cited references 12

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          Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis.

          Acute myocardial infarction (MI) due to coronary artery occlusion is accompanied by a pathological remodeling response that includes hypertrophic cardiac growth and fibrosis, which impair cardiac contractility. Previously, we showed that cardiac hypertrophy and heart failure are accompanied by characteristic changes in the expression of a collection of specific microRNAs (miRNAs), which act as negative regulators of gene expression. Here, we show that MI in mice and humans also results in the dysregulation of specific miRNAs, which are similar to but distinct from those involved in hypertrophy and heart failure. Among the MI-regulated miRNAs are members of the miR-29 family, which are down-regulated in the region of the heart adjacent to the infarct. The miR-29 family targets a cadre of mRNAs that encode proteins involved in fibrosis, including multiple collagens, fibrillins, and elastin. Thus, down-regulation of miR-29 would be predicted to derepress the expression of these mRNAs and enhance the fibrotic response. Indeed, down-regulation of miR-29 with anti-miRs in vitro and in vivo induces the expression of collagens, whereas over-expression of miR-29 in fibroblasts reduces collagen expression. We conclude that miR-29 acts as a regulator of cardiac fibrosis and represents a potential therapeutic target for tissue fibrosis in general.
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            TGF-β/Smad3 signaling promotes renal fibrosis by inhibiting miR-29.

            TGF-β/Smad3 signaling promotes fibrosis, but the development of therapeutic interventions involving this pathway will require the identification and ultimate targeting of downstream fibrosis-specific genes. In this study, using a microRNA microarray and real-time PCR, wild-type mice had reduced expression of miR-29 along with the development of progressive renal fibrosis in obstructive nephropathy. In contrast, Smad3 knockout mice had increased expression of miR-29 along with the absence of renal fibrosis in the same model of obstruction. In cultured fibroblasts and tubular epithelial cells, Smad3 mediated TGF-β(1)-induced downregulation of miR-29 by binding to the promoter of miR-29. Furthermore, miR-29 acted as a downstream inhibitor and therapeutic microRNA for TGF-β/Smad3-mediated fibrosis. In vitro, overexpression of miR-29b inhibited, but knockdown of miR-29 enhanced, TGF-β(1)-induced expression of collagens I and III by renal tubular cells. Ultrasound-mediated gene delivery of miR-29b either before or after established obstructive nephropathy blocked progressive renal fibrosis. In conclusion, miR-29 is a downstream inhibitor of TGF-β/Smad3-mediated fibrosis and may have therapeutic potential for diseases involving fibrosis.
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              Renal medullary microRNAs in Dahl salt-sensitive rats: miR-29b regulates several collagens and related genes.

              MicroRNAs are endogenous repressors of gene expression. We examined microRNAs in the renal medulla of Dahl salt-sensitive rats and consomic SS-13(BN) rats. Salt-induced hypertension and renal injury in Dahl salt-sensitive rats, particularly medullary interstitial fibrosis, have been shown previously to be substantially attenuated in SS-13(BN) rats. Of 377 microRNAs examined, 5 were found to be differentially expressed between Dahl salt-sensitive rats and consomic SS-13(BN) rats receiving a high-salt diet. Real-time PCR analysis demonstrated that high-salt diets induced substantial upregulation of miR-29b in the renal medulla of SS-13(BN) rats but not in SS rats. miR-29b was predicted to regulate 20 collagen genes, matrix metalloproteinase 2 (Mmp2), integrin beta1 (Itgb1), and other genes related to the extracellular matrix. Expression of 9 collagen genes and Mmp2 was upregulated by a high-salt diet in the renal medulla of SS rats, but not in SS-13(BN) rats, an expression pattern opposite to miR-29b. Knockdown of miR-29b in the kidneys of SS-13(BN) rats resulted in upregulation of several collagen genes. miR-29b reduced expression levels of several collagen genes and Itgb1 in cultured rat renal medullary epithelial cells. Moreover, miR-29b suppressed the activity of luciferase when the reporter gene was linked to a 3'-untranslated segment of collagen genes Col1a1, Col3a1, Col4a1, Col5a1, Col5a2, Col5a3, Col7a1, Col8a1, Mmp2, or Itgb1 but not Col12a1. The result demonstrated broad effects of miR-29b on a large number of collagens and genes related to the extracellular matrix and suggested involvement of miR-29b in the protection from renal medullary injury in SS-13(BN) rats.
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                Author and article information

                Journal
                Annals of Neurology
                Ann Neurol.
                Wiley
                03645134
                November 2016
                November 2016
                October 19 2016
                : 80
                : 5
                : 741-753
                Affiliations
                [1 ]Inserm U1161; Genetics and Physiopathology of Cerebrovascular Diseases; Paris France
                [2 ]Inserm U1161; Paris7 Diderot University, Sorbonne Paris Cité; Paris France
                [3 ]AP-HP Lariboisière Neurology Department; CERVCO Reference Center for Rare Vascular Diseases of the Eye and Brain; Paris France
                [4 ]Neurology department, CHRU of Lille, Lille 2 University, Inserm U1171; Lille France
                [5 ]AP-HP Lariboisière Molecular Genetics Department; CERVCO Reference Center for Rare Vascular Diseases of the Eye and Brain; Paris France
                [6 ]Neurology Department; Saint Philibert Hospital; Lomme France
                [7 ]Neurology Department; Gonesse Hospital; Gonesse France
                [8 ]Neurology Department; Henri Mondor Hospital; Creteil France
                [9 ]Neurology Department; Valenciennes Hospital; Valenciennes France
                [10 ]Neurology Department; Coulommiers Hospital; Coulommiers France
                [11 ]Institute of Neuropathology; University Medical Center; Hamburg Germany
                [12 ]Department of Neurology; University Hospital Schleswig-Holstein; Kiel Germany
                [13 ]Neurology Department; Agen Hospital; Agen France
                [14 ]CMAbio3, Applied Microscopy and Biology Center; University of Caen; Caen France
                [15 ]Institute of Cardiovascular and Medical Sciences; College of Medical, Veterinary and Life Sciences, University of Glasgow; Glasgow United Kingdom
                [16 ]Pathology Department; CHRU of Caen, University of Caen Normandy; Inserm U1075
                Article
                10.1002/ana.24782
                27666438
                © 2016

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