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Protein arginine methyltranferase-1 induces ER stress and epithelial-mesenchymal transition in renal tubular epithelial cells and contributes to diabetic nephropathy.

Biochimica et biophysica acta. Molecular basis of disease (2019-06-15)
Yin-Yin Chen, Xiao-Fei Peng, Guo-Yong Liu, Jin-Song Liu, Lin Sun, Hong Liu, Li Xiao, Li-Yu He
ABSTRACT

In this study, we examined the association of PRMT1 with ER stress and epithelial-mesenchymal transition (EMT), two critical pathogenic mechanisms leading to DN development, in proximal tubular epithelial cells (PTECs). The level of PRMT1 was compared between the serum from DN patients and healthy individuals by ELISA, and between renal tissues of DN mice and normal mice using RT-qPCR and immunohistochemistry. Using high-glucose-treated PTEC cell line, HK2 cells as the model system, the significance of PRMT1 in ER stress and EMT was assessed by shRNA targeting PRMT1 (sh-PRMT1) and/or by overexpressing PRMT1. Mechanistic studies focused on three major pathways controlling ER stress: protein kinase R-like ER kinase (PERK), inositol requiring-1α (IRE1α), and activating transcription factor 6 (ATF6). PRMT1 was up-regulated in the serum of DN patients and renal tissues of DN mice. High glucose administration induced elevation of PRMT1 expression in HK2 cells in vitro, accompanied with ER stress and EMT activation. PRMT1 knockdown attenuated high glucose-induced ER stress and apoptosis by inactivating PERK and ATF6, but not IRE1α. PRMT1 activated ATF6 by recruiting H4R3me2as to the promoter. Furthermore, PRMT1-induced ER stress was concomitant with the activation of an EMT-like state. Specifically, inhibition of ATF6, but not PERK blocked PRMT1-induced EMT in high-glucose-treatment HK2 cells. By activating ER stress, PRMT1 essentially regulates the apoptosis and EMT of PTECs in response to diabetic milieu. Thus, targeting PRMT1 may alleviate both tissue injury and renal fibrosis, and thus benefit the treatment of DN.

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Solketal methacrylate, 50 wt. % in dichloromethane, contains ~280 ppm 4-tert-butylcatechol as inhibitor