miR-200b precursor can ameliorate renal tubulointerstitial fibrosis.
Members of the miR-200 family of micro RNAs (miRNAs) have been shown to inhibit epithelial-mesenchymal transition (EMT). EMT of tubular epithelial cells is the mechanism by which renal fibroblasts are generated. Here we show that miR-200 family members inhibit transforming growth factor-beta (TGF-beta)-induced EMT of tubular cells. Unilateral ureter obstruction (UUO) is a common model of EMT of tubular cells and subsequent tubulointerstitial fibrosis. In order to examine the role of miR-200 family members in tubulointerstitial fibrosis, their expression was investigated in the kidneys of UUO mice. The expression of miR-200 family miRNAs was increased in a time-dependent manner, with induction of miR-200b most pronounced. To clarify the effect of miR-200b on tubulointerstitial fibrosis, we injected miR-200b precursor intravenously. A single injection of 0.5 nM miR-200b precursor was sufficient to inhibit the increase of collagen types I, III and fibronectin in obstructed kidneys, and amelioration of fibrosis was confirmed by observation of the kidneys with Azan staining. miR-200 family members have been previously shown to inhibit EMT by reducing the expression of ZEB-1 and ZEB-2 which are known repressors of E-cadherin. We demonstrated that expression of ZEB-1 and ZEB-2 was increased after ureter obstruction and that administration of the miR-200b precursor reversed this effect. In summary, these results indicate that miR-200 family is up-regulated after ureter obstruction, miR-200b being strongly induced, and that miR-200b ameliorates tubulointerstitial fibrosis in obstructed kidneys. We suggest that members of the miR-200 family, and miR-200b specifically, might constitute novel therapeutic targets in kidney disease.
Department of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo, Japan. OBA-2IM@h.u-tokyo.ac.jp
Shigeyoshi
S
Oba
Shintaro
S
Kumano
Etsu
E
Suzuki
Hiroaki
H
Nishimatsu
Masao
M
Takahashi
Hajime
H
Takamori
Masatoshi
M
Kasuya
Yousuke
Y
Ogawa
Kenichiro
K
Sato
Kenjiro
K
Kimura
Yukio
Y
Homma
Yasunobu
Y
Hirata
Toshiro
T
Fujita
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D017931:DNA Primers; D058750:Epithelial-Mesenchymal Transition; D005355:Fibrosis; D005455:Fluorescent Antibody Technique; D006801:Humans; D007674:Kidney Diseases / Q000517:prevention & control*; D007684:Kidney Tubules / Q000473:pathology*; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D016133:Polymerase Chain Reaction
D017931:DNA Primers; C533896:MIRN200 microRNA, human; D035683:MicroRNAs