Department of Pharmacology and Toxicology, Faculty of Pharmacy, Menoufia University, 32511 Menoufia, Egypt.
Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo, Egypt.
Life Sci. 2023 Jun 15;323:121697. doi: 10.1016/j.lfs.2023.121697. Epub 2023 Apr 14.
this study aims to explore the effect of androgen receptor (AR) blockade by flutamide on some renal pathologic changes such as inflammation, apoptosis, and fibrosis in male rats.
Firstly, we investigated the potential effect of AR blockade on renal inflammatory intermediates including IL-1β, IL-6, TNF-α, NF-Қβ proteins, and the renal gene expression of NF-Қβ. Besides inflammation, we also assessed the apoptosis pathways including the caspases 3 & 9, mTOR, pAKT proteins, and BAX gene expression. Besides inflammation and apoptosis pathways, we also investigated the effect of androgen blockade on renal fibrosis intermediates including vimentin, TGFβ-1, α-SMA, MMP-9, collagen type-III, collagen type-IV, and the renal expression of the col1A1 gene. Besides previous pathological pathways, we assessed the expression of chloride channel protein-5 (ClC-5), as an important regulator of many renal pathological changes. Finally, we assessed the impact of previous pathological changes on renal function at biochemical and pathological levels.
We found that AR blockade by flutamide was associated with the down-regulation of renal inflammation, apoptosis, and fibrosis markers. It was associated with expression down-regulation of IL-1β & IL-6, TNF-α, NF-Қβ, caspases 3 & 9, mTOR, MMP-9, collagens, TGFβ-1, and α-SMA. Away from down-regulation, we also found that AR blockade has upregulated ClC-5 and pAKT proteins.
AR is a major player in androgens-induced nephrotoxicity. AR blockade downregulates renal fibrosis, inflammation, and apoptosis pathways. It may be helpful as a strategy for alleviation of renal side effects associated with some drugs. However; this needs further investigations.
本研究旨在探讨雄激素受体（AR）阻断剂氟他胺对雄性大鼠某些肾脏病变的影响，如炎症、细胞凋亡和纤维化。
首先，我们研究了 AR 阻断对包括白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）、NF-κB 蛋白在内的肾脏炎症介质以及 NF-κB 基因表达的潜在影响。除了炎症，我们还评估了包括半胱天冬酶 3 和 9（caspases 3 & 9）、mTOR、pAKT 蛋白和 BAX 基因表达在内的细胞凋亡途径。除了炎症和细胞凋亡途径，我们还研究了雄激素阻断对肾脏纤维化介质的影响，包括波形蛋白、转化生长因子-β1（TGFβ-1）、α-平滑肌肌动蛋白（α-SMA）、基质金属蛋白酶 9（MMP-9）、III 型胶原、IV 型胶原和 col1A1 基因在肾脏的表达。除了上述病理途径外，我们还评估了氯离子通道蛋白-5（ClC-5）的表达，ClC-5 作为许多肾脏病理变化的重要调节剂。最后，我们评估了在生化和病理水平上先前的病理变化对肾功能的影响。
我们发现，氟他胺对 AR 的阻断与肾脏炎症、细胞凋亡和纤维化标志物的下调有关。它与 IL-1β 和 IL-6、TNF-α、NF-κB、caspases 3 & 9、mTOR、MMP-9、胶原、TGFβ-1 和 α-SMA 的表达下调有关。除了下调，我们还发现 AR 阻断上调了 ClC-5 和 pAKT 蛋白。
AR 是雄激素诱导肾毒性的主要参与者。AR 阻断下调肾脏纤维化、炎症和细胞凋亡途径。它可能有助于缓解某些药物相关的肾脏副作用。然而，这需要进一步的研究。
