Saleh Mohamed A, Awad Ahmed M, Ibrahim Tarek M, Abu-Elsaad Nashwa M
Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, UAE.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 33516, Egypt.
Pharmaceuticals (Basel). 2020 Nov 17;13(11):397. doi: 10.3390/ph13110397.
The therapeutic use of numerous pharmacological agents may be limited due to their nephrotoxicity and associated kidney injury. The aim of our study is to test the hypothesis that the blockade of tyrosine kinase-linked receptors signaling protects against chemically induced nephrotoxicity. To test our hypothesis, we investigated sunitinib as an inhibitor for tyrosine kinase signaling for both vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptors (PDGFR) against adenine-induced nephrotoxicity. Four groups of adult male Swiss albino mice were investigated: normal group, adenine group, sunitinib group, and the adenine+sunitinib group that received concurrent administration for both adenine and sunitinib. Kidney function and oxidative stress biomarkers were analyzed. Tubular injury and histopathological changes were examined. Renal expression of B-cell lymphoma-2 (Bcl-2), the tumor suppressor p53, transforming growth factor beta-1 (TGF-β1), phospho-extracellular signal-regulated kinase 1/2 (p-ERK1/2), and phospho-signal transducer and activator of transcription (phospho-STAT3) were measured. The results obtained showed significant improvement ( 0.05) in kidney function and antioxidant biomarkers in the adenine+sunitinib group. Kidney fibrosis and tubular injury scores were significantly ( 0.05) less in the adenine+sunitinib group and that of p53 expression as well. Furthermore, sunitinib decreased ( 0.5) renal levels of TGF-β1, p-ERK1/2, and phospho-STAT3 while elevating Bcl-2 expression score. In conclusion, sunitinib diminished adenine-induced nephrotoxicity through interfering with profibrogenic pathways, activating anti-apoptotic mechanisms, and possessing potential antioxidant capabilities.
许多药物制剂的治疗用途可能因其肾毒性及相关肾损伤而受到限制。我们研究的目的是验证酪氨酸激酶连接受体信号传导的阻断可预防化学诱导的肾毒性这一假说。为验证我们的假说，我们研究了舒尼替尼作为血管内皮生长因子受体（VEGFR）和血小板衍生生长因子受体（PDGFR）酪氨酸激酶信号传导抑制剂对腺嘌呤诱导的肾毒性的作用。对四组成年雄性瑞士白化小鼠进行了研究：正常组、腺嘌呤组、舒尼替尼组以及同时给予腺嘌呤和舒尼替尼的腺嘌呤+舒尼替尼组。分析了肾功能和氧化应激生物标志物。检查了肾小管损伤和组织病理学变化。测定了肾组织中B细胞淋巴瘤-2（Bcl-2）、肿瘤抑制因子p53、转化生长因子β1（TGF-β1）、磷酸化细胞外信号调节激酶1/2（p-ERK1/2）以及磷酸化信号转导子和转录激活子（磷酸化STAT3）的表达。所得结果显示，腺嘌呤+舒尼替尼组的肾功能和抗氧化生物标志物有显著改善（P<0.05）。腺嘌呤+舒尼替尼组的肾纤维化和肾小管损伤评分显著降低（P<0.05），p53表达评分也显著降低。此外，舒尼替尼降低了（P<0.05）肾组织中TGF-β1、p-ERK1/2和磷酸化STAT3的水平，同时提高了Bcl-2表达评分。总之，舒尼替尼通过干扰促纤维化途径、激活抗凋亡机制以及具有潜在的抗氧化能力，减轻了腺嘌呤诱导的肾毒性。
