EGF Receptor Inhibition Alleviates Hyperuricemic Nephropathy
EGF Receptor Inhibition Alleviates Hyperuricemic Nephropathy
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EGF 受体抑制可缓解高尿酸血症肾病
DOI：
10.1681/asn.2014080793
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发表时间：
2015-11-01
影响因子：
13.6
通讯作者：
Zhuang, Shougang
中科院分区：
文献类型：
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作者：
Liu, Na;Wang, Li;Zhuang, Shougang
高尿酸血症是CKD的独立危险因素，并导致肾纤维化。在这项研究中，我们研究了EGF受体（EGFR）抑制对高尿酸血症肾病（HN）发生的影响及其机制。在通过喂食腺嘌呤和氧钾的混合物诱导的HN大鼠模型中，EGFR磷酸化增加和严重的肾小球硬化和肾间质纤维化是明显的，伴随着肾功能障碍和尿微量白蛋白排泄增加。给予吉非替尼（一种高选择性EGFR抑制剂）可预防肾功能不全，减少尿微量白蛋白，并抑制肾间质成纤维细胞活化和细胞外蛋白表达。吉非替尼治疗还可抑制高尿酸血症诱导的TGF-β 1和NF-κ B信号通路的激活以及肾脏中多种促纤维化细胞因子/趋化因子的表达。此外，吉非替尼治疗抑制黄嘌呤氧化酶活性，介导尿酸的产生，并保留有机阴离子转运蛋白1和3的表达，促进尿酸排泄在高尿酸血症大鼠的肾脏。因此，阻断EGFR可以通过抑制TGF-β 1信号传导和炎症以及促进减少体内尿酸积累的分子过程来减弱HN的发展。
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-beta 1 and NF-kappa B signaling pathways and expression of multiple profibrogenic cytokines/chennokines 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-beta 1 signaling and inflammation and promotion of the molecular processes that reduce uric acid accumulation in the body.