MicroRNA-22 Is a Master Regulator of Bone Morphogenetic Protein-7/6 Homeostasis in the Kidney

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 k...

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Bibliographic Details
Published in:The Journal of biological chemistry 2013-12, Vol.288 (51), p.36202-36214
Main Authors: Long, Jianyin, Badal, Shawn S., Wang, Yin, Chang, Benny H.J., Rodriguez, Antony, Danesh, Farhad R.
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Bone Morphogenetic Protein (BMP)
Bone Morphogenetic Protein 6 - genetics
Bone Morphogenetic Protein 6 - metabolism
Bone Morphogenetic Protein 7 - genetics
Bone Morphogenetic Protein 7 - metabolism
Fibrosis
Fibrosis - metabolism
Gene Regulation
Homeostasis
Kidney
Kidney - metabolism
Kidney - pathology
Mice
Mice, Inbred BALB C
Mice, Knockout
MicroRNA
MicroRNAs - genetics
MicroRNAs - metabolism
Molecular Bases of Disease
Molecular Sequence Data
Response Elements
Signal Transduction
Transcription, Genetic
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Summary: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. Background: BMPs have emerged as key regulators of kidney fibrosis. Results: Deletion of miR-22 attenuated renal fibrosis via direct targeting of BMP-7/6. BMP-7/6 in turn transcriptionally regulates miR-22 expression. Conclusion: miR-22 and BMP-7/6 form a negative feedback circuit. Significance: The present study is the first to report the effect of miR-22 on BMP signaling and kidney fibrosis.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M113.498634