Biochemistry Department-Faculty of Pharmacy (Boys), Al-Azhar University, Almokhayam Aldaem Street, 6th Province, Nasr City, Cairo, 13465, Egypt.
Pharmacology and Toxicology Department-Faculty of Pharmacy, Kafrelsheikh University, Kafr El Sheikh, Egypt.
Environ Sci Pollut Res Int. 2020 May;27(14):16189-16202. doi: 10.1007/s11356-020-08073-z. Epub 2020 Feb 28.
Polycyclic aromatic hydrocarbons (PAHs)/aryl hydrocarbon receptor (AhR) regulate the expression of target genes, including drug transporter genes which harbor xenobiotic response element (XRE) in their promoter regions. Thus, PAHs/AhR could alter the toxicokinetic profile of many nephrotoxic drugs, including aminoglycosides. In the current study, we investigated the expression and localization of AhR and megalin in rat kidney. Furthermore, we investigated whether AhR and its ligands could modulate the expression of megalin and consequently the gentamicin-induced nephrotoxicity (GN) in rats. Both megalin and AhR receptors are expressed in the proximal tubules of the rat kidney. Treatment with AhR agonist benzo(a)pyrene aggravated GN as indicated by a significant increase in serum creatinine, BUN, KIM1, NAGL, CD-86, and urinary albumin/creatinine ratio. On the other hand, treatment with AhR antagonist resveratrol ameliorated GN as manifested by a pronounced decrease in the aforementioned parameters. The effects of AhR ligands on GN were associated with altered expression of megalin receptor.
多环芳烃（PAHs）/芳烃受体（AhR）调节靶基因的表达，包括在其启动子区域中含有外源性反应元件（XRE）的药物转运蛋白基因。因此，PAHs/AhR 可以改变许多肾毒性药物的毒代动力学特征，包括氨基糖苷类药物。在本研究中，我们研究了 AhR 和 megalin 在大鼠肾脏中的表达和定位。此外，我们还研究了 AhR 及其配体是否可以调节 megalin 的表达，从而调节氨基糖苷类药物诱导的大鼠肾毒性（GN）。在大鼠肾脏的近端小管中均表达 megalin 和 AhR 受体。AhR 激动剂苯并（a）芘的处理加剧了 GN，表现为血清肌酐、BUN、KIM1、NAGL、CD-86 和尿白蛋白/肌酐比显著增加。另一方面，AhR 拮抗剂白藜芦醇的处理改善了 GN，表现为上述参数明显下降。AhR 配体对 GN 的影响与 megalin 受体表达的改变有关。
