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

AIM: 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. MAIN METHODS: Firstly, we investigated the potential effect of AR blockade on renal inflammatory intermediates including IL-1ß, IL-6, TNF-α, NF-Òšß proteins, and the renal gene expression of NF-Қß. 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, TGFß-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 FINDINGS: 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-1ß & IL-6, TNF-α, NF-Қß, caspases 3 & 9, mTOR, MMP-9, collagens, TGFß-1, and α-SMA. Away from down-regulation, we also found that AR blockade has upregulated ClC-5 and pAKT proteins. SIGNIFICANCE: 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.

Pioglitazone ameliorates high fat diet-induced hypertension and induces catechol o-methyl transferase expression in rats.

Our study aimed to investigate the effect of pioglitazone (PIO) on the obesity-associated metabolic effects and whether this effect is associated with modulation of catechol O-methyl transferase (COMT) expression in the high fat diet (HFD) induced obese rats. Male Wistar rats fed HFD were used to evaluate the effect of PIO on obesity-associated hypertension and the expression of COMT. The HFD-induced obesity was confirmed by the change in body weights, the fasting serum insulin (FSI) which assessed by ELISA, homeostasis model assessment - insulin resistance (HOMA-IR), fasting blood glucose (FBG), oral glucose tolerance test (OGTT) and lipid profile which were determined by colorimetric methods. Plasma epinephrine (EP) and norepinephrine (NE) were determined by ELISA and the systolic blood pressure (SBP) was recorded using the tail-cuff method. COMT expression was assessed by quantitative real time-polymerase chain reaction (qRT-PCR), and western blotting. The HFD-induced obesity was associated with glucose intolerance, derangement of the lipid profile, increased SBP, reduced COMT expression with a concomitant increase in plasma catecholamines. Most importantly, treatment with PIO ameliorated the HFD-induced metabolic changes, improved the lipid profile, reduced SBP, increased COMT expression, and reduced plasma catecholamines. Treatment with PIO reversed HFD-induced glucose intolerance and the associated metabolic derangement. In addition, these effects of PIO were associated with up-regulating COMT expression with a subsequent reduction in plasma catecholamines levels.

Androgen/androgen receptor affects gentamicin-induced nephrotoxicity through regulation of megalin expression.

AIM: Investigation whether androgen/androgen receptor (AR) might regulate megalin expression and/or functionality and thus affecting Gentamicin-induced nephrotoxicity (GIN). MAIN METHODS: Male Wistar rats were treated with gentamicin with/out AR ligands (testosterone as agonist and flutamide as antagonist). Megalin expression in the kidney tissues was determined by real-time RT-PCR and western blot. Besides, megalin functionality was assessed using immunofluorescence imaging of fluorescein isothiocyanate (FITC) conjugated bovine serum albumin (BSA) (FITC-BSA). The effects of different treatments on the kidney were assessed at the structural level by histopathological evaluation and the biochemical level by colorimetric assay of blood urea nitrogen (BUN), serum creatinine (SCr) and urinary albumin/creatinine (A/C) ratio, besides, kidney expression of neutrophil gelatinase-associated lipocalin (NGAL) by immunoblotting. KEY FINDINGS: Our results revealed that treatment with testosterone either alone or combined with gentamicin increased megalin expression at mRNA and protein levels as well as at the functional level. These effects were paralleled by increased GIN as manifested by increased SCr, BUN, A/C ratio, renal expression of NGAL or histopathological changes. On the other hand, treatment with flutamide ameliorated GIN and megalin expression and functionality. Computational analysis of megalin promotor revealed the presence of multiple response elements that mediate androgen response. SIGNIFICANCE: Androgen/AR regulates megalin expression at the transcriptional level and consequently GIN. This may explain the sexual dimorphism in GIN and might represent a druggable target for treatment or prevention of GIN.