Arecoline-induced pro-fibrotic proteins in LLC-PK1 cells are dependent on c-Jun N-terminal kinase

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• 作者：Sheng-Hsuan Lin^a ; ¹ ; Shean-Jaw Chiou^b ; ¹ ; Wan-Ting Ho^b ; Chao-Tang Chuang^a ; Lea-Yea Chuang^b ; ^{chuangly@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Jinn-Yuh Guh^c ; ^d ; ^{guhjy@kmu.edu.tw" class="auth_mail" title="E-mail the corresponding author}
• 关键词：CKD ; chronic kidney disease ; TGF-β ; transforming growth factor-β ; JNK ; c-Jun N-terminal kinase ; PAI1 ; plasminogen activator inhibitor-1 ; COX2 ; cyclooxygenase 2 ; AN ; areca nut ; ERK ; extracellular signal-regulated kinase ; DMSO ; dimethylsulfoxide ; MTT ; 3-(4 ; 5-dimethylthiazol-2-yl)-2 ; 5-diphenyl tetrazolium Bromide ; SEM ; standard errors of the mean
• 刊名：Toxicology
• 出版年：2016
• 出版时间：17 February 2016
• 年：2016
• 卷：344-346
• 期：Complete
• 页码：53-60
• 全文大小：1953 K

文摘

Areca nut (AN) chewing is associated with chronic kidney disease (CKD). However, the molecular mechanisms of AN-induced CKD are not known. Thus, we studied the effects of arecoline, a major alkaloid of AN, on proximal tubule (LLC-PK1) cells in terms of cytotoxicity, fibrosis, transforming growth factor-β (TGF-β) and c-Jun N-terminal kinase (JNK).

We found that arecoline dose (0.1–0.5 mM) and time (24–72 h)-dependently induced cytotoxicity without causing cell death. Arecoline (0.25 mM) also time-dependently (24–72 h) increased fibronectin and plasminogen activator inhibitor-1 (PAI1) protein expressions. Arecoline (0.25 mM) time-dependently (24–72 h) increased TGF-β gene transcriptional activity and supernatant levels of active TGF-β1. Moreover, arecoline (0.25 mM) activated JNK while SP600125 (a JNK inhibitor) attenuated arecoline-induced TGF-β gene transcriptional activity. SP600125, but not SB431542 (a TGF-β receptor type I kinase inhibitor), attenuated arecoline-induced fibronectin and PAI1 protein expressions. Finally, tubulointerstitial fibrosis occurred and renal cortical expressions of fibronectin and PAI1 proteins increased in arecoline-fed mice at 24 weeks.

We concluded that arecoline induced tubulointerstitial fibrosis in mice while arecoline-induced TGF-β and pro-fibrotic proteins (fibronectin, PAI1) are dependent on JNK in LLC-PK1 cells.