title: MicroRNA-22 is a master regulator of bone morphogenetic protein-7/6 homeostasis in the kidney.
abstract: Accumulating evidence suggests that microRNAs (miRNAs) contribute to a myriad of kidney diseases. However, the regulatory role of miRNAs on the key molecules implicated in kidney fibrosis remains poorly understood. Bone morphogenetic protein-7 (BMP-7) and its related BMP-6 have recently emerged as key regulators of kidney fibrosis. Using the established unilateral ureteral obstruction (UUO) model of kidney fibrosis as our experimental model, we examined the regulatory role of miRNAs on BMP-7/6 signaling. By analyzing the potential miRNAs that target BMP-7/6 in silica, we identified miR-22 as a potent miRNA targeting BMP-7/6. We found that expression levels of BMP-7/6 were significantly elevated in the kidneys of the miR-22 null mouse. Importantly, mice with targeted deletion of miR-22 exhibited attenuated renal fibrosis in the UUO model. Consistent with these in vivo observations, primary renal fibroblast isolated from miR-22-deficient UUO mice demonstrated a significant increase in BMP-7/6 expression and their downstream targets. This phenotype could be rescued when cells were transfected with miR-22 mimics. Interestingly, we found that miR-22 and BMP-7/6 are in a regulatory feedback circuit, whereby not only miR-22 inhibits BMP-7/6, but miR-22 by itself is induced by BMP-7/6. Finally, we identified two BMP-responsive elements in the proximal region of miR-22 promoter. These findings identify miR-22 as a critical miRNA that contributes to renal fibrosis on the basis of its pivotal role on BMP signaling cascade.
authors.affiliation: From the Nephrology Section, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Jianyin
authors.initials: J
authors.lastname: Long
authors.forename: Shawn S
authors.initials: SS
authors.lastname: Badal
authors.forename: Yin
authors.initials: Y
authors.lastname: Wang
authors.forename: Benny H J
authors.initials: BH
authors.lastname: Chang
authors.forename: Antony
authors.initials: A
authors.lastname: Rodriguez
authors.forename: Farhad R
authors.initials: FR
authors.lastname: Danesh
mesh_terms: D000818:Animals; D001483:Base Sequence; D055418:Bone Morphogenetic Protein 6 / Q000235:genetics / Q000378:metabolism*; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics / Q000378:metabolism*; D005355:Fibrosis / Q000378:metabolism; D006706:Homeostasis; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D020218:Response Elements; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: C525817:Bmp6 protein, mouse; D055418:Bone Morphogenetic Protein 6; D055419:Bone Morphogenetic Protein 7; D035683:MicroRNAs; C574876:Mirn22 microRNA, mouse; C525820:bmp7 protein, mouse
keywords: Bone Morphogenetic Protein (BMP); Fibrosis; Gene Regulation; Kidney; MicroRNA