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MicroRNA21 promotes interstitial fibrosis via targeting DDAH1: a potential role in renal fibrosis

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Abstract

Scarring of the kidney directly promotes loss of kidney function. A thorough understanding of renal fibrosis at the molecular level is urgently needed. One prominent microRNA, miR-21, was previously reported to be up-regulated in renal fibrosis, but its mechanism is unclear. In the present study, an unbiased search for downstream messenger RNA targets of miR-21 using the HK-2 human tubular epithelial cell line was performed. Effects of the target gene in renal fibrosis and underlying mechanism were explored. Results show that forced expression of miR-21 significantly increased cell apoptosis, interstitial deposition, and decreased E-cadherin level of the HK-2 cells. Conversely, inhibition of miR-21 promoted the opposite effects. We identified that miR-21 directly interacted with the 3′-untranslated region of the suppressor of dimethylarginine dimethylaminohydrolase 1 (DDAH1) by dual-luciferase assay. Moreover, pcDNA3.1-DDAH1 pretreatment could effectively reduce α-SMA, collagen I, fibronectin expression, and promoted E-cadherin expression, as well as inhibiting HK-2 cell apoptosis, while all those effects can be attenuated by pretreatment with the Wnt/β-catenin signaling activator Licl. Taken together, our results suggest that miR-21 may regulate renal fibrosis by the Wnt pathway via directly targeting DDAH1. Therefore, this study may provide novel strategies for the development of renal fibrosis therapy.

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Abbreviations

DDAH1:

Dimethylarginine dimethylaminohydrolase 1

CKD:

Chronic kidney disease

ESRD:

End-stage renal disease

miRs:

microRNAs

RISC:

RNA-induced silencing complex

UUO:

Unilateral ureteral obstruction

ADMA:

Asymmetric dimethylarginine

HK-2:

Human tubular epithelial cells

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Acknowledgments

This work was supported by grants from the Natural Science Foundation of China (No. 81260114) and the Natural Science Foundation Project of Jiangxi Province (No. 20142BAB205007).

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    Authors and Affiliations

    1. Department of Nephrology, the 94th Hospital of Chinese People’s Liberation Army, Changcheng Hospital affiliated to Nanchang University, Jinggangshan Road 1028, Nanchang, 330002, Jiangxi, People’s Republic of China

      Xiu-Juan Liu, Zhen Wang, Yan-yan Yu, Xin Zou & Li-hong Xu

    2. Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, 100039, People’s Republic of China

      Quan Hong

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    1. Xiu-Juan Liu
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    Correspondence to Xiu-Juan Liu.

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    Xiu-Juan Liu and Quan Hong contributed equally to this work.

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    Liu, XJ., Hong, Q., Wang, Z. et al. MicroRNA21 promotes interstitial fibrosis via targeting DDAH1: a potential role in renal fibrosis. Mol Cell Biochem 411, 181–189 (2016). https://doi.org/10.1007/s11010-015-2580-2

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