Department of Pediatric Medicine, Emory University, and Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
PLoS One. 2013;8(1):e54738. doi: 10.1371/journal.pone.0054738. Epub 2013 Jan 18.
Nephrotic syndrome is associated with up-regulation of the heparin-binding epidermal growth factor (HB-EGF). Erlotinib blocks the activation of the epidermal growth factor receptor (EGFR) in response to HB-EGF. This study investigates the effect of Erlotinib on the progression of proteinuria, renal dysfunction, and salt retention in doxorubicin treated nephrotic rats. Male rats were divided into 3 pair-fed groups (n = 13/group) as follows: Control rats (Ctrl); rats receiving intravenous doxorubicin (Dox); and rats receiving intravenous doxorubicin followed by daily oral Erlotinib (Dox + Erl). Upon establishment of high grade proteinuria, urine sodium and creatinine clearance were measured. Kidney tissue was dissected and analyzed for γ-epithelial sodium channel (γENaC), sodium-potassium -chloride co-transporter 2 (NKCC2), sodium chloride co-transporter (NCC), aquaporin 2 (AQP2), and EGFR abundances using western blot. Creatinine clearance was preserved in the Dox + Erl rats as compared to the Dox group (in ml/min: Ctrl: 5.2±.5, Dox: 1.9±0.3, Dox + Erl: 3.6±0.5). Despite a minimal effect on the degree of proteinuria, Erlotinib prevented salt retention (Urinary Na in mEq/d: Ctrl: 2.2±0.2, Dox: 1.8±0.3, Dox + Erl: 2.2±0.2). The cleaved/uncleaved γENaC ratio was increased by 41±16% in the Dox group but unchanged in the Dox + Erl group when compared to Ctrl. The phosphorylated EGFR/total EGFR ratio was reduced by 74±7% in the Dox group and by 77±4% in the Dox + Erl group. In conclusion, Erlotinib preserved renal function and prevented salt retention in nephrotic rats. The observed effects do not appear to be mediated by direct blockade of EGFR.
肾病综合征与肝素结合表皮生长因子（HB-EGF）的上调有关。厄洛替尼可阻断 HB-EGF 对表皮生长因子受体（EGFR）的激活。本研究探讨了厄洛替尼对阿霉素诱导的肾病大鼠蛋白尿进展、肾功能障碍和盐潴留的影响。雄性大鼠分为 3 组（每组 13 只）：对照组（Ctrl）；接受静脉注射阿霉素的大鼠（Dox）；以及接受静脉注射阿霉素后每天口服厄洛替尼的大鼠（Dox+Erl）。当建立高等级蛋白尿时，测量尿钠和肌酐清除率。分离肾脏组织并使用 Western blot 分析γ-上皮钠通道（γENaC）、钠-钾-氯共转运体 2（NKCC2）、氯化钠共转运体（NCC）、水通道蛋白 2（AQP2）和 EGFR 的丰度。与 Dox 组相比，Dox+Erl 组的肌酐清除率得到保留（以 ml/min 计：Ctrl：5.2±0.5，Dox：1.9±0.3，Dox+Erl：3.6±0.5）。尽管厄洛替尼对蛋白尿程度的影响很小，但它可预防盐潴留（尿钠 mEq/d：Ctrl：2.2±0.2，Dox：1.8±0.3，Dox+Erl：2.2±0.2）。与 Ctrl 相比，Dox 组的裂解/未裂解 γENaC 比值增加了 41±16%，而 Dox+Erl 组则没有变化。Dox 组的磷酸化 EGFR/总 EGFR 比值降低了 74±7%，Dox+Erl 组降低了 77±4%。总之，厄洛替尼可维持肾病大鼠的肾功能并预防盐潴留。观察到的作用似乎不是通过直接阻断 EGFR 介导的。
