Abstract：
The present study aimed to investigate the role of α and β-adrenergic receptors (βARs) in mediation or modulation of the dexamethasone-induced nephrotoxicity by using different pharmacological interventions. Nephrotoxicity was induced by subcutaneous injection of dexamethasone (10 mg/kg) for 7 days in Wistar albino rats. Eight groups were used: control; dexamethasone; carvedilol; phenylephrine; carvedilol and phenylephrine; propranolol; doxazosin; propranolol and doxazosin. At the end of experiment, rats were euthanized and blood, urine and kidney samples were collected. Serum and urinary creatinine and urinary total protein levels were measured. Also, the renal tissue levels of diacylglycerol (DAG); Akt kinase activity, malondialdehyde (MDA), NADPH oxidase 2 (NOX2), transforming growth factor-β (TGF-β), Wnt3A and β-catenin were recorded. Furthermore, histopathological and β-arrestin2-immunohistochemical examinations of renal tissues were performed. Results: Dexamethasone induced glomerular damage, proteinuria, renal oxidative stress and upregulated the renal Wnt/β-arrestin2/β-catenin pathway and the profibrotic signals. Blocking the α1 and βARs by carvedilol reduced the dexamethasone-induced nephrotoxicity. Pre-injection of phenylephrine did not reduce the reno-protective action of carvedilol. Blocking the βARs only by propranolol reduced the dexamethasone-induced nephrotoxicity to the same extent of carvedilol group. Blocking the α1ARs only by doxazosin reduced dexamethasone-induced nephrotoxicity to a higher extent than other treatments. However, combined use of propranolol and doxazosin did not synergize the reno-protective effects of doxazosin. Conclusion: Dexamethasone induces nephrotoxicity, possibly, by upregulating the Wnt/β-arrestin2/β-catenin pathway. Blocking either α1ARs or βARs can effectively protect against the dexamethasone-induced nephrotoxicity. However, combined blocking of α1ARs and βARs does not synergize the reno-protective effects.
摘要：
本研究旨在通过使用不同的药物干预措施来研究α和β-肾上腺素能受体（βARs）在地塞米松诱导的肾毒性的介导或调节中的作用。通过在Wistar白化病大鼠中皮下注射地塞米松（10mg/kg）7天诱导肾毒性。使用了八组：对照组；地塞米松；卡维地洛；去氧肾上腺素；卡维地洛和去氧肾上腺素；普萘洛尔；多沙唑嗪；普萘洛尔和多沙唑嗪。实验结束时,老鼠被安乐死和血液，收集尿液和肾脏样本。测量血清和尿肌酐和尿总蛋白水平。此外，二酰甘油（DAG）的肾组织水平;Akt激酶活性，丙二醛（MDA），NADPH氧化酶2(NOX2),转化生长因子-β（TGF-β），记录Wnt3A和β-catenin。此外，对肾组织进行组织病理学和β-arrestin2免疫组织化学检查。结果:地塞米松诱导肾小球损伤,蛋白尿,肾脏氧化应激并上调肾脏Wnt/β-arrestin2/β-catenin通路和促纤维化信号。卡维地洛阻断α1和βARs可降低地塞米松诱导的肾毒性。预注射去氧肾上腺素不会降低卡维地洛的肾保护作用。仅通过普萘洛尔阻断βARs可将地塞米松诱导的肾毒性降低到与卡维地洛组相同的程度。与其他治疗相比，仅通过多沙唑嗪阻断α1ARs可在更高的程度上降低地塞米松诱导的肾毒性。然而,普萘洛尔和多沙唑嗪的联合使用没有协同多沙唑嗪的肾保护作用.结论:地塞米松具有肾毒性,可能,通过上调Wnt/β-arrestin2/β-catenin通路。阻断α1ARs或βARs均可有效防止地塞米松诱导的肾毒性。然而,联合阻断α1ARs和βARs不会协同作用。
