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MKP2 inhibits TGF-β1-induced epithelial-to-mesenchymal transition in renal tubular epithelial cells through a JNK-dependent pathway.
Clin Sci (Lond). 2018 11 15; 132(21):2339-2355.CS

Abstract

Epithelial-to-mesenchymal transition (EMT) is a phenotypic conversion that plays a crucial role in renal fibrosis leading to chronic renal failure. Mitogen-activated protein kinase phosphatase 2 (MKP2) is a member of the dual-specificity MKPs that regulate the MAP kinase pathway involved in transforming growth factor-β1 (TGF-β1)-induced EMT. However, the function of MKP2 in the regulation of EMT and the underlying mechanisms are still largely unknown. In the present study, we detected the expression of MKP2 in an animal model of renal fibrosis and evaluated the potential role of MKP2 in tubular EMT induced by TGF-β1. We found that the expression of MKP2 was up-regulated in the tubular epithelial of unilateral ureter obstruction rats. Meanwhile, we also demonstrated that TGF-β1 up-regulated MKP2 expression in NRK-52E cells during their EMT phenotype acquisition. Importantly, overexpression of MKP2 inhibited c-Jun amino terminal kinase (JNK) signaling and partially reversed EMT induced by TGF-β1. Moreover, reducing MKP2 expression enhanced JNK phosphorylation, promoted the E-cadherin suppression and induced α-SMA expression and fibronectin secretion in response to TGF-β1, which could be rescued by a JNK inhibitor. These results provide the first evidence that MKP2 is a negative feedback molecule induced by TGF-β1, and MKP2 overexpression inhibits TGF-β1-induced EMT through the JNK signaling pathway. MKP2 could be a promising target to be used in gene therapy for renal fibrosis.

Authors+Show Affiliations

Department of Nephrology, Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China gucchh2013@126.com lzzkiki@126.com.Pathological Experiment Center, Henan University of Traditional Chinese Medicine, Zhengzhou, China.Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.Pediatric Urology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China gucchh2013@126.com lzzkiki@126.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30322849

Citation

Li, Zhenzhen, et al. "MKP2 Inhibits TGF-β1-induced Epithelial-to-mesenchymal Transition in Renal Tubular Epithelial Cells Through a JNK-dependent Pathway." Clinical Science (London, England : 1979), vol. 132, no. 21, 2018, pp. 2339-2355.
Li Z, Liu X, Tian F, et al. MKP2 inhibits TGF-β1-induced epithelial-to-mesenchymal transition in renal tubular epithelial cells through a JNK-dependent pathway. Clin Sci (Lond). 2018;132(21):2339-2355.
Li, Z., Liu, X., Tian, F., Li, J., Wang, Q., & Gu, C. (2018). MKP2 inhibits TGF-β1-induced epithelial-to-mesenchymal transition in renal tubular epithelial cells through a JNK-dependent pathway. Clinical Science (London, England : 1979), 132(21), 2339-2355. https://doi.org/10.1042/CS20180602
Li Z, et al. MKP2 Inhibits TGF-β1-induced Epithelial-to-mesenchymal Transition in Renal Tubular Epithelial Cells Through a JNK-dependent Pathway. Clin Sci (Lond). 2018 11 15;132(21):2339-2355. PubMed PMID: 30322849.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - MKP2 inhibits TGF-β1-induced epithelial-to-mesenchymal transition in renal tubular epithelial cells through a JNK-dependent pathway. AU - Li,Zhenzhen, AU - Liu,Xianghua, AU - Tian,Fengyan, AU - Li,Ji, AU - Wang,Qingwei, AU - Gu,Chaohui, Y1 - 2018/11/13/ PY - 2018/07/11/received PY - 2018/10/13/revised PY - 2018/10/15/accepted PY - 2018/10/17/pubmed PY - 2019/9/17/medline PY - 2018/10/17/entrez KW - epithelial-to-mesenchymal transition KW - mitogen-activated protein kinases KW - renal fibrosis KW - transforming growth factors SP - 2339 EP - 2355 JF - Clinical science (London, England : 1979) JO - Clin Sci (Lond) VL - 132 IS - 21 N2 - Epithelial-to-mesenchymal transition (EMT) is a phenotypic conversion that plays a crucial role in renal fibrosis leading to chronic renal failure. Mitogen-activated protein kinase phosphatase 2 (MKP2) is a member of the dual-specificity MKPs that regulate the MAP kinase pathway involved in transforming growth factor-β1 (TGF-β1)-induced EMT. However, the function of MKP2 in the regulation of EMT and the underlying mechanisms are still largely unknown. In the present study, we detected the expression of MKP2 in an animal model of renal fibrosis and evaluated the potential role of MKP2 in tubular EMT induced by TGF-β1. We found that the expression of MKP2 was up-regulated in the tubular epithelial of unilateral ureter obstruction rats. Meanwhile, we also demonstrated that TGF-β1 up-regulated MKP2 expression in NRK-52E cells during their EMT phenotype acquisition. Importantly, overexpression of MKP2 inhibited c-Jun amino terminal kinase (JNK) signaling and partially reversed EMT induced by TGF-β1. Moreover, reducing MKP2 expression enhanced JNK phosphorylation, promoted the E-cadherin suppression and induced α-SMA expression and fibronectin secretion in response to TGF-β1, which could be rescued by a JNK inhibitor. These results provide the first evidence that MKP2 is a negative feedback molecule induced by TGF-β1, and MKP2 overexpression inhibits TGF-β1-induced EMT through the JNK signaling pathway. MKP2 could be a promising target to be used in gene therapy for renal fibrosis. SN - 1470-8736 UR - https://www.unboundmedicine.com/medline/citation/30322849/MKP2_inhibits_TGF_β1_induced_epithelial_to_mesenchymal_transition_in_renal_tubular_epithelial_cells_through_a_JNK_dependent_pathway_ L2 - https://portlandpress.com/clinsci/article-lookup/doi/10.1042/CS20180602 DB - PRIME DP - Unbound Medicine ER -