title: EGF Receptor Inhibition Alleviates Hyperuricemic Nephropathy.
abstract: Hyperuricemia is an independent risk factor for CKD and contributes to kidney fibrosis. In this study, we investigated the effect of EGF receptor (EGFR) inhibition on the development of hyperuricemic nephropathy (HN) and the mechanisms involved. In a rat model of HN induced by feeding a mixture of adenine and potassium oxonate, increased EGFR phosphorylation and severe glomerular sclerosis and renal interstitial fibrosis were evident, accompanied by renal dysfunction and increased urine microalbumin excretion. Administration of gefitinib, a highly selective EGFR inhibitor, prevented renal dysfunction, reduced urine microalbumin, and inhibited activation of renal interstitial fibroblasts and expression of extracellular proteins. Gefitinib treatment also inhibited hyperuricemia-induced activation of the TGF-β1 and NF-κB signaling pathways and expression of multiple profibrogenic cytokines/chemokines in the kidney. Furthermore, gefitinib treatment suppressed xanthine oxidase activity, which mediates uric acid production, and preserved expression of organic anion transporters 1 and 3, which promotes uric acid excretion in the kidney of hyperuricemic rats. Thus, blocking EGFR can attenuate development of HN via suppression of TGF-β1 signaling and inflammation and promotion of the molecular processes that reduce uric acid accumulation in the body.
authors: Department of Nephrology and szhuang@lifespan.org naliubrown@hotmail.com.
authors: Na
authors: N
authors: Liu
authors: Department of Nephrology and.
authors: Li
authors: L
authors: Wang
authors: Department of Medicine, Rhode Island Hospital and Brown University School of Medicine, Providence, Rhode Island;
authors: Tao
authors: T
authors: Yang
authors: Research Center for Translational Medicine Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China;
authors: Chongxiang
authors: C
authors: Xiong
authors: Department of Nephrology and.
authors: Liuqing
authors: L
authors: Xu
authors: Department of Nephrology and.
authors: Yingfeng
authors: Y
authors: Shi
authors: Department of Nephrology and.
authors: Wenfang
authors: W
authors: Bao
authors: Institute of Health Sciences, Chinese Academy of Sciences, Shanghai, China;
authors: Y Eugene
authors: YE
authors: Chin
authors: Department of Pediatrics, Women & Infants Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island; and.
authors: Shi-Bin
authors: SB
authors: Cheng
authors: Department of Nephrology and.
authors: Haidong
authors: H
authors: Yan
authors: School of Life Science and Technology, Advanced Institute of Translational Medicine, Tongji University, Shanghai, China.
authors: Andong
authors: A
authors: Qiu
authors: Department of Nephrology and Research Center for Translational Medicine Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; szhuang@lifespan.org naliubrown@hotmail.com.
authors: Shougang
authors: S
authors: Zhuang
mesh_terms: D000818:Animals; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis / Q000473:pathology; D000077156:Gefitinib; D033461:Hyperuricemia / Q000188:drug therapy* / Q000378:metabolism*; D007249:Inflammation; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000378:metabolism*; D008297:Male; D010766:Phosphorylation; D011799:Quinazolines / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012307:Risk Factors; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014527:Uric Acid / Q000737:chemistry
chemical_list: D018925:Chemokines; D016207:Cytokines; D011799:Quinazolines; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014527:Uric Acid; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: Cell signaling; TGF-beta; chronic kidney disease; fibroblast; interstitial fibrosis