Long Noncoding RNA Arid2-IR Is a Novel Therapeutic Target for Renal Inflammation.
Increasing evidence shows that microRNAs play an important role in kidney disease. However, functions of long noncoding RNAs (lncRNAs) in kidney diseases remain undefined. We have previously shown that TGF-β1 plays a diverse role in renal inflammation and fibrosis and Smad3 is a key mediator in this process. In this study, we used RNA-sequencing to identify lncRNAs related to renal inflammation and fibrosis in obstructive nephropathy induced in Smad3 wild-type and knockout mice. We found that Arid2-IR was a Smad3-associated lncRNA as a Smad3 binding site was found in the promoter region of Arid2-IR and deletion of Smad3 abolished upregulation of Arid2-IR in the diseased kidney. In vitro knockdown of Arid2-IR from tubular epithelial cells produced no effect on TGF-β-induced Smad3 signaling and fibrosis but inhibited interleukin-1β-stimulated NF-κB-dependent inflammatory response. In contrast, overexpression of Arid2-IR promoted interleukin-1β-induced NF-κB signaling and inflammatory cytokine expression without alteration of TGF-β1-induced fibrotic response. Furthermore, treatment of obstructed kidney with Arid2-IR shRNA blunted NF-κB-driven renal inflammation without effect on TGF-β/Smad3-mediated renal fibrosis. Thus, Arid2-IR is a novel lncRNA that functions to promote NF-κB-dependent renal inflammation. Blockade of Arid2-IR may represent a novel and specific therapy for renal inflammatory disease.
Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China; Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Qin
Q
Zhou
Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
Xiao R
XR
Huang
Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China; Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Jianwen
J
Yu
Department of Nephrology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China. Electronic address: yuxq@mail.sysu.edu.cn.
Xueqing
X
Yu
Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China. Electronic address: hylan@cuhk.edu.hk.
Hui Y
HY
Lan
D000818:Animals; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D015316:Genetic Therapy / Q000379:methods*; D007249:Inflammation / Q000628:therapy*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D007674:Kidney Diseases / Q000235:genetics / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics*; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
C512512:Arid2 protein, mouse; D053583:Interleukin-1beta; D016328:NF-kappa B; D062085:RNA, Long Noncoding; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta