MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-β-induced collagen expression via inhibition of E-box repressors
- 27 February 2007
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 104 (9), 3432-3437
- https://doi.org/10.1073/pnas.0611192104
Abstract
Key features of diabetic nephropathy (DN) include the accumulation of extracellular matrix proteins such as collagen 1-α 1 and -2 (Col1a1 and -2). Transforming growth factor β1 (TGF-β), a key regulator of these extracellular matrix genes, is increased in mesangial cells (MC) in DN. By microarray profiling, we noted that TGF-β increased Col1a2 mRNA in mouse MC (MMC) but also decreased mRNA levels of an E-box repressor, δEF1. TGF-β treatment or short hairpin RNAs targeting δEF1 increased enhancer activity of upstream E-box elements in the Col1a2 gene. TGF-β also decreased the expression of Smad-interacting protein 1 (SIP1), another E-box repressor similar to δEF1. Interestingly, we noted that SIP1 is a target of microRNA-192 (miR-192), a key miR highly expressed in the kidney. miR-192 levels also were increased by TGF-β in MMC. TGF-β treatment or transfection with miR-192 decreased endogenous SIP1 expression as well as reporter activity of a SIP1 3′ UTR-containing luciferase construct in MMC. Conversely, a miR-192 inhibitor enhanced the luciferase activity, confirming SIP1 to be a miR-192 target. Furthermore, miR-192 synergized with δEF1 short hairpin RNAs to increase Col1a2 E-box-luc activity. Importantly, the in vivo relevance was noted by the observation that miR-192 levels were enhanced significantly in glomeruli isolated from streptozotocin-injected diabetic mice as well as diabetic db/db mice relative to corresponding nondiabetic controls, in parallel with increased TGF-β and Col1a2 levels. These results uncover a role for miRs in the kidney and DN in controlling TGF-β-induced Col1a2 expression by down-regulating E-box repressors.Keywords
This publication has 34 references indexed in Scilit:
- Oncomirs — microRNAs with a role in cancerNature Reviews Cancer, 2006
- ERK-dependent Signaling Pathway and Transcriptional Factor Ets-1 Regulate Matrix Metalloproteinase-9 Production in Transforming Growth Factor-β1 Stimulated Glomerular PodocytesCellular Physiology and Biochemistry, 2005
- Silencing of microRNAs in vivo with ‘antagomirs’Nature, 2005
- Regulation by let-7 and lin-4 miRNAs Results in Target mRNA DegradationCell, 2005
- The functions of animal microRNAsNature, 2004
- MicroRNAs: small RNAs with a big role in gene regulationNature Reviews Genetics, 2004
- In Vivo Chromatin Remodeling Events Leading to Inflammatory Gene Transcription under Diabetic ConditionsPublished by Elsevier BV ,2004
- Role of Smad4 on TGF-β–induced extracellular matrix stimulation in mesangial cellsKidney International, 2003
- Sp1 and Smad Proteins Cooperate to Mediate Transforming Growth Factor-β1-induced α2(I) Collagen Expression in Human Glomerular Mesangial CellsPublished by Elsevier BV ,2001
- TGF-β: Regulation of extracellular matrixKidney International, 1992