Nanjing First Hospital, Nanjing Medical University, Nanjing, ChinaChina
Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, ChinaChina
Department of Medicine, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA Chronic kidney disease (CKD) is a clinical syndrome characterized by a gradual loss of kidney function that persists for >3 months with health implications and affects nearly 500 million people worldwide. Diabetes and hypertension are the 2 most common causes of CKD, which account for up to two-thirds of the cases.
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Chronic kidney disease (CKD) is a clinical syndrome characterized by a gradual loss of kidney function that persists for >3 months with health implications and affects nearly 500 million people worldwide. Diabetes and hypertension are the 2 most common causes of CKD, which account for up to two-thirds of the cases.1-3 Accumulating evidence has shown that hyperuricemia is tightly associated with the pathogenesis of CKD.1-4 Hyperuricemic nephropathy is a condition characterized by glomerular hypertension, arteriolosclerosis, and tubule interstitial fibrosis. Prior studies demonstrate that decreasing uric acid levels delays the development of CKD and slows its progression and uric acid is an independent predictor of future development of CKD.1-4 The mechanistic processes by which hyperuricemia induces chronic renal injury involve deposition of uric acid crystals in the collecting duct of the kidney, renal angiotension system activation, oxidative stress, tubular epithelial cell transition and inflammation.4-7
Keywords: oxidative; hyperuricemia; demonstrate
ISSN 2380-0445 http://dx.doi.org/10.17140/NPOJ-3-e006 Open Journal Editorial The Epidermal Growth Factor Receptor: * *Corresponding author A Potential Therapeutic Target in Chronic Shi-Bin Cheng, MD, PhD Assistant Professor Department of Medicine Kidney Disease Warren Alpert Medical School of Brown University 1 2 3* Providence, RI 02903, USA Zijun Liu, MD, PhD1; Na Liu, MD, PhD2; Shi-Bin Cheng, MD, PhD3* E-mail: shibin_cheng@brown.edu 1Nanjing First Hospital, Nanjing Medical University, Nanjing, China Volume 3 : Issue 1 2Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Article Ref. #: 1000NPOJ3e006 Shanghai, China 3Department of Medicine, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA Article History th Received: September 5th, 2015 th Accepted: September 5th, 2015 Chronic kidney disease (CKD) is a clinical syndrome characterized by a gradual loss th Published: September 8th, 2016 of kidney function that persists for >3 months with health implications and affects nearly 500 million people worldwide. Diabetes and hypertension are the 2 most common causes of CKD, 1-3 which account for up to two-thirds of the cases.1-3 Accumulating evidence has shown that hyper- Citation 1-4 uricemia is tightly associated with the pathogenesis of CKD.1-4 Hyperuricemic nephropathy is Liu Z, Liu N, Cheng S-B. The epidermal growth factor recep- a condition characterized by glomerular hypertension, arteriolosclerosis, and tubule interstitial tor: A potential therapeutic tar- fibrosis. Prior studies demonstrate that decreasing uric acid levels delays the development of get in chronic kidney disease.
CKD and slows its progression and uric acid is an independent predictor of future development Nephrol Open J. 2016; 3(1): e1-e2. 1-4 of CKD. The mechanistic processes by which hyperuricemia induces chronic renal injury doi: 10.17140/NPOJ-3-e006 involve deposition of uric acid crystals in the collecting duct of the kidney, renal angiotension 4-7 system activation, oxidative stress, tubular epithelial cell transition and inflammation.4-7 The epidermal growth factor receptor (EGFR) is a member of the ErbB family of receptors. EGFR is activated by binding of its specific ligands such as epidermal growth factor (EGF) and transforming growth factor α (TGFα). Additionally, EGFR can be transactivated by cytokines, oxidants as well as indirectly via activation of G protein-coupled receptors such as 8-10 angiotension II receptor and G protein-coupled estrogen receptor-1 (GPER-1).8-10 Upon activa- tion, EGFR undergoes dimerization, a transition from an inactive monomeric form to an ac- tive homodimer. EGFR dimerization promotes its intrinsic intracellular protein-tyrosine kinase activity, which results in autophosphorylation of several tyrosine residues in the C-terminal domain of EGFR. This autophosphorylation initiates several signal transduction cascades such as the mitogen-activated protein kinases (MAPK), protein kinase B (PKB) also known as Akt and Jun amino-terminal kinases (JNK) pathways, regulating cell migration, adhesion, and pro- 8,9 liferation.8,9 Numerous studies have shown that EGFR activation contributes to chronic renal in- 4,10 4 jury and glomerular sclerosis. Intriguingly, a recent study by Liu et al reported that EGFR activation was critically involved in uric acid-induced chronic renal injury in a rat model of hyperuricemic nephropathy. Using this model, they demonstrated that blockage of EGFR by gefitinib, a drug that specially inhibits EGFR activation and is clinically used for treating vari- ous cancers, alleviated renal fibrosis and renal tubular injury and inhibited activation of renal interstitial fibroblast, a pathological process that initiates the development of renal fibrosis and Copyright 4 promotes its progression. Mechanistically, inhibition of EGFR abrogated the expression of ©2016 Cheng S-B. This is an open TGF-β and phosphorylation of Smad3 (a downstream molecule of TGF-β), and blocked NF-kB access article distributed under the pathway activation and macrophage infiltration in the kidney of hyperuricemic rat. In addi- Creative Commons Attribution 4.0 International License (CC BY 4.0), tion, gfitinib treatment decreased release of various proinflammatory cytokines/chemokines which permits unrestricted use, including TGFα, interleukin 1 beta (IL-1β), monocyte chemoattractant protein-1 (MCP-1) and distribution, and reproduction in 4 RANTES. Furthermore, blockage of EGFR reduced serum uric acid levels through inhibiting any medium, provided the original the activity of the enzyme xanthine oxidase, a key enzyme for the production of uric acid, as work is properly cited.
well as through preventing the downregulation of urate transporters, organic anion transporter ISSN 2380-0445 http://dx.doi.org/10.17140/NPOJ-3-e006 4 4 1 (OAT1) and OAT3.4 Collectively, Liu and colleagues4 have demonstrated for the first time that EGFR activity contributes to the pathogenesis of hyperuricemic nephropathy and that EGFR blockage alleviates development of hyperuricemia-induced nephropathy through blocking TGF-β signaling pathway, inhibiting inflammatory response, and reducing uric acid production. Thus, EGFR may serve as a therapeutic target for treating uric acid-associated CKD.
CONFLICTS OF INTEREST The authors declare that they have no conflicts of interest.