期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2007
卷号：104
期号：9
页码：3432-3437
DOI：10.1073/pnas.0611192104
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Key features of diabetic nephropathy (DN) include the accumulation of extracellular matrix proteins such as collagen 1-{alpha} 1 and -2 (Col1a1 and -2). Transforming growth factor [beta]1 (TGF-[beta]), a key regulator of these extracellular matrix genes, is increased in mesangial cells (MC) in DN. By microarray profiling, we noted that TGF-[beta] increased Col1a2 mRNA in mouse MC (MMC) but also decreased mRNA levels of an E-box repressor, {delta}EF1. TGF-[beta] treatment or short hairpin RNAs targeting {delta}EF1 increased enhancer activity of upstream E-box elements in the Col1a2 gene. TGF-[beta] also decreased the expression of Smad-interacting protein 1 (SIP1), another E-box repressor similar to {delta}EF1. 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-[beta] in MMC. TGF-[beta] 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 {delta}EF1 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-[beta] and Col1a2 levels. These results uncover a role for miRs in the kidney and DN in controlling TGF-[beta]-induced Col1a2 expression by down-regulating E-box repressors.
