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Bicalutamide Elicits Renal Damage by Causing Mitochondrial Dysfunction via ROS Damage and Upregulation of HIF-1.

ABSTRACT: Combined androgen blockade using bicalutamide (Bic) is a therapeutic choice for treating prostate cancer (PCa). However, even at regular clinical dosages, Bic frequently shows adverse effects associated with cardiovascular and renal damage. Previously, we found that Bic selectively damaged mesangial cells compared to tubular cells and in an in vivo rat model, we also found renal damage caused by Bic. In the present study, a rat mesangial cell model was used to further the investigation. Results indicated that Bic enhanced lactate dehydrogenase release, reactive oxygen species (ROS) production, lysosome population and kidney injury molecule-1 and decreased N-cadherin. Bic elicited mitochondrial swelling and reduced the mitochondrial potential, resulting in severe suppression of the oxygen consumption rate (OCR), maximum respiration and ATP production. The hypoxia-inducible factor (HIF)-1 transcriptional activity and messenger RNA were significantly upregulated in dose-dependent manners. The HIF-1 protein reached a peak value at 24 h then rapidly decayed. BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 and cleaved caspase-3 were dose-dependently upregulated by Bic (60 M) and that eventually led to cell apoptosis. It is suggested that Bic induces renal damage via ROS and modulates HIF-1 pathway and clinically, some protective agents like antioxidants are recommended for co-treatment.

SUBMITTER: Chen KC

PROVIDER: S-EPMC7247665 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Bicalutamide Elicits Renal Damage by Causing Mitochondrial Dysfunction <i>via</i> ROS Damage and Upregulation of HIF-1.

Chen Kuan-Chou KC Chen Chang-Rong CR Chen Chang-Yu CY Tzou Kai-Yi KY Peng Chiung-Chi CC Peng Robert Y RY

International journal of molecular sciences 20200511 9

Combined androgen blockade using bicalutamide (Bic) is a therapeutic choice for treating prostate cancer (PCa). However, even at regular clinical dosages, Bic frequently shows adverse effects associated with cardiovascular and renal damage. Previously, we found that Bic selectively damaged mesangial cells compared to tubular cells and in an in vivo rat model, we also found renal damage caused by Bic. In the present study, a rat mesangial cell model was used to further the investigation. Results ...[more]

PMID: 32403414

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Project description:BackgroundRecent animal studies have shown that mitochondrial dysfunction initiates and accelerates renal injury in sepsis, but its role in sepsis remains unknown. Mitochondrial stress or dying cells can lead to fragmentation of the mitochondrial genome, which is considered a surrogate marker of mitochondrial dysfunction. Therefore, we evaluated the efficiency of urinary mitochondrial DNA (UmtDNA) as a marker of renal dysfunction during sepsis-induced acute kidney injury (AKI).MethodsWe isolated DNA from plasma and urine of patients. mtDNA levels were quantified by quantitative PCR. Sepsis patients were divided into no AKI, mild AKI, and severe AKI groups according to RIFLE criteria. Additionally, cecal ligation and puncture (CLP) was established in rats to evaluate the association between UmtDNA and mitochondrial function.ResultsA total of 52 (49.5%) developed AKI among enrolled sepsis patients. Increased systemic mtDNA did not correlate with systemic inflammation or acute renal dysfunction in sepsis patients, while AKI did not have an additional effect on circulating mtDNA levels. In contrast, UmtDNA was significantly enriched in severe AKI patients compared with that in the mild AKI or no AKI group, positively correlated with plasma creatinine, urinary neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1, and inversely with the estimated glomerular filtration rate. Additionally, UmtDNA increased in rats following CLP-induced sepsis. UmtDNA was predictive of AKI development and correlated with plasma creatinine and blood urea nitrogen in the rat sepsis model. Finally, the UmtDNA level was inversely correlated with the cortical mtDNA copy number and relative expression of mitochondrial gene in the kidney.ConclusionAn elevated UmtDNA level correlates with mitochondrial dysfunction and renal injury in sepsis patients, indicating renal mitochondrial injury induced by sepsis. Therefore, UmtDNA may be regarded as a valuable biomarker for the occurrence of AKI and the development of mitochondria-targeted therapies following sepsis-induced AKI.

Project description:Background: Doxorubicin (Dox) can induce endotheliotoxicity and damage the vascular endothelium (VE). The most principle mechanism might be excess reactive oxygen species (ROS) generation. Nevertheless, the characteristics of ROS generation, downstream mechanisms, and target organelles in Dox-induced endotheliotoxicity have yet to be elucidated. Methods and Results: In order to explore the related problems, the VE injury models were established in mice and human umbilical vein endothelial cells (HUVECs) by Dox-induced endotheliotoxicity. Results showed that the activities of lactate dehydrogenase (LDH) and creatine kinase of mice's serum increased after injected Dox. The thoracic aortic strips' endothelium-dependent dilation was significantly impaired, seen noticeable inflammatory changes, and brown TUNEL-positive staining in microscopy. After Dox-treated, HUVECs viability lowered, LDH and caspase-3 activities, and apoptotic cells increased. Both intracellular/mitochondrial ROS generation significantly increased, and intracellular ROS generation lagged behind mitochondria. HUVECs treated with Dox plus ciclosporin A (CsA) could basically terminate ROS burst, but plus edaravone (Eda) could only delay or inhibit, but could not completely cancel ROS burst. Meanwhile, the expression of endothelial nitric oxide synthase (eNOS) decreased, especially phosphorylation of eNOS significantly. Then nitric oxide content decreased, the mitochondrial function was impaired, mitochondrial membrane potential (MMP) impeded, mitochondrial swelled, mitochondrial permeability transition pore (mPTP) was opened, and cytochrome C was released from mitochondria into the cytosol. Conclusion: Dox produces excess ROS in the mitochondria, thereby weakens the MMP, opens mPTP, activates the ROS-induced ROS release mechanism, induces ROS burst, and leads to mitochondrial dysfunction, which in turn damages VE. Therefore, interrupting any step of the cycles, as mentioned above can end the related vicious cycle and prevent the occurrence and development of injury.

Project description:Mycophenolic acid (MPA) may cause gastrointestinal adverse effects by damaging the intestinal epithelial barrier, the underlying mechanisms remain elusive. Studies have demonstrated that oxidative stress caused by reactive oxygen species (ROS) is linked to tight junction (TJ) proteins and apoptosis, both of which cause abnormalities in intestinal barrier function. Mitochondria, one of the main sources of ROS and abnormally high levels of ROS are linked to mitochondrial dysfunction. The aim of this study was to investigate whether MPA induces intestinal barrier dysfunction through regulation of the mitochondrial ROS. MPA-induced intestinal injury model in Kunming mice and Caco-2 cells. The effect of MPA on Caco-2 cell viability was measured by MTT; tissue diamine oxidase and endotoxin expression were determined by ELISA; expression of total proteins of ZO-1, occludin, Bax, Bcl-2, and mitochondrial proteins of Cytochrome C and Bax was measured by Western blot; and the localization of Cytochrome C with MitoTraker was observed by immunofluorescence staining. Caco-2 cell apoptosis, ROS levels, and mitochondrial membrane potential were detected by flow cytometry, while intramitochondrial ROS levels were observed by MitoSOX fluorescence staining. The results showed that MPA increased intracellular and mitochondrial ROS production to promote oxidative stress and the antioxidant NAC effectively restored ZO-1 and occludin expressions, reduced apoptosis in intestinal epithelial cells. Furthermore, we found that low concentrations of MPA caused mitochondrial damage, induced hyperpolarization of the mitochondrial membrane potential and the translocation of Cytochrome C and Bax proteins from the cytoplasm to the mitochondria. The mitochondrial protectant SS-31 reduces intracellular and intramitochondrial ROS, upregulates TJ, and reduces apoptosis. Our studies suggest that MPA-induced intestinal barrier dysfunction in vivo and in vitro is mediated, at least in part, by impairing mitochondrial function and promoting oxidative stress.

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Bicalutamide Elicits Renal Damage by Causing Mitochondrial Dysfunction via ROS Damage and Upregulation of HIF-1.

Publications

Bicalutamide Elicits Renal Damage by Causing Mitochondrial Dysfunction <i>via</i> ROS Damage and Upregulation of HIF-1.

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