title: Loss of MicroRNA-192 promotes fibrogenesis in diabetic nephropathy.
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-beta1 decreased miR-192 expression. Overexpression of miR-192 suppressed expression of the E-Box repressors ZEB1 and ZEB2, thereby opposing TGF-beta-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-beta-mediated downregulation of E-cadherin in PTCs.
authors.affiliation: Institute of Nephrology, Cardiff University, Heath Park Campus, Cardiff, UK.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Krupa
authors.forename: Robert
authors.initials: R
authors.lastname: Jenkins
authors.forename: Dong Dong
authors.initials: DD
authors.lastname: Luo
authors.forename: Aled
authors.initials: A
authors.lastname: Lewis
authors.forename: Aled
authors.initials: A
authors.lastname: Phillips
authors.forename: Donald
authors.initials: D
authors.lastname: Fraser
mesh_terms: D001706:Biopsy; D015820:Cadherins / Q000235:genetics; D002460:Cell Line; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000502:physiology; D005919:Glomerular Filtration Rate / Q000502:physiology; D006801:Humans; D017403:In Situ Hybridization; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000473:pathology*; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009395:Nephritis, Interstitial / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D015820:Cadherins; C546783:MIRN192 microRNA, human; D035683:MicroRNAs; D016212:Transforming Growth Factor beta