Loss of MicroRNA-192 Promotes Fibrogenesis in Diabetic Nephropathy
- 1 March 2010
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of the American Society of Nephrology
- Vol. 21 (3), 438-447
- https://doi.org/10.1681/asn.2009050530
Abstract
The role of microRNAs (miRs), which are endogenous RNA oligonucleotides that regulate gene expression, in diabetic nephropathy is unknown. Here, we performed expression profiling of cultured proximal tubular cells (PTCs) under high-glucose and control conditions. We identified expression of 103 of 328 microRNAs but did not observe glucose-induced changes in expression. Next, we performed miR expression profiling in pooled RNA from formalin-fixed, paraffin-embedded tissue from renal biopsies. We studied three groups of patients with established diabetic nephropathy and detected 103 of 365 miRs. Two miRs differed by more than two-fold between progressors and nonprogressors, and 12 miRs differed between late presenters and other biopsies. We noted the greatest change in miR-192 expression, which was significantly lower in late presenters. Furthermore, in individual biopsies, low expression of miR-192 correlated with tubulointerstitial fibrosis and low estimated GFR. In vitro, treatment of PTCs with TGF-β1 decreased miR-192 expression. Overexpression of miR-192 suppressed expression of the E-Box repressors ZEB1 and ZEB2, thereby opposing TGF-β–mediated downregulation of E-cadherin. In summary, loss of miR-192 expression associates with increased fibrosis and decreased estimated GFR in diabetic nephropathy in vivo, perhaps by enhancing TGF-β–mediated downregulation of E-cadherin in PTCs.Keywords
This publication has 34 references indexed in Scilit:
- MicroRNA expression profiles predictive of human renal allograft statusProceedings of the National Academy of Sciences of the United States of America, 2009
- SMAD proteins control DROSHA-mediated microRNA maturationNature, 2008
- A reciprocal repression between ZEB1 and members of the miR‐200 family promotes EMT and invasion in cancer cellsEMBO Reports, 2008
- The miR-200 Family Inhibits Epithelial-Mesenchymal Transition and Cancer Cell Migration by Direct Targeting of E-cadherin Transcriptional Repressors ZEB1 and ZEB2Journal of Biological Chemistry, 2008
- The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2Genes & Development, 2008
- Differential Regulation of Epithelial and Mesenchymal Markers by δEF1 Proteins in Epithelial–Mesenchymal Transition Induced by TGF-βMolecular Biology of the Cell, 2007
- TGFβ1 regulation of vimentin gene expression during differentiation of the C2C12 skeletal myogenic cell line requires Smads, AP-1 and Sp1 family membersBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2007
- MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-β-induced collagen expression via inhibition of E-box repressorsProceedings of the National Academy of Sciences, 2007
- Transforming growth factor-β employs HMGA2 to elicit epithelial–mesenchymal transitionThe Journal of cell biology, 2006
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001