Androgen receptor blockade by flutamide down-regulates renal fibrosis, inflammation, and apoptosis pathways in male rats

Abstract

Aimthis 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. Main methodsFirstly, 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. Key findingsWe 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. SignificanceAR 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.