MiR-382 targeting of kallikrein 5 contributes to renal inner medullary interstitial fibrosis.
Previously we have shown that microRNA miR-382 can facilitate loss of renal epithelial characteristics in cultured cells. This study examined the in vivo role of miR-382 in the development of renal interstitial fibrosis in a mouse model. Unilateral ureteral obstruction was used to induce renal interstitial fibrosis in mice. With 3 days of unilateral ureteral obstruction, expression of miR-382 in the obstructed kidney was increased severalfold compared with sham-operated controls. Intravenous delivery of locked nucleic acid-modified anti-miR-382 blocked the increase in miR-382 expression and significantly reduced inner medullary fibrosis. Expression of predicted miR-382 target kallikrein 5, a proteolytic enzyme capable of degrading several extracellular matrix proteins, was reduced with unilateral ureteral obstruction. Anti-miR-382 treatment prevented the reduction of kallikrein 5 in the inner medulla. Furthermore, the protective effect of the anti-miR-382 treatment against fibrosis was abolished by renal knockdown of kallikrein 5. Targeting of kallikrein 5 by miR-382 was confirmed by 3'-untranslated region luciferase assay. These data support a completely novel mechanism in which miR-382 targets kallikrein 5 and contributes to the development of renal inner medullary interstitial fibrosis. The study provided the first demonstration of an in vivo functional role of miR-382 in any species and any organ system.
Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Alison J
AJ
Kriegel
Yong
Y
Liu
Brett
B
Cohen
Kristie
K
Usa
Youhua
Y
Liu
Mingyu
M
Liang
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D007610:Kallikreins / Q000235:genetics / Q000378:metabolism*; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*
D020413:3' Untranslated Regions; D035683:MicroRNAs; D007610:Kallikreins; C495973:Klk5 protein, mouse