Androgen/androgen receptor affects gentamicin-induced nephrotoxicity through regulation of megalin expression
| Autor: | Bakheet E. M. Elsadek, Osama Abd Al-Motaal Mansour, Shady Allam, Salama Abdou Salama, Elsayed G.E. Elsakka, Adel I. Abd Elaziz, Ahmad Mohamed Elsisi |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty medicine.drug_class Lipocalin urologic and male genital diseases 030226 pharmacology & pharmacy General Biochemistry Genetics and Molecular Biology Flutamide Nephrotoxicity 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine medicine Animals Testosterone General Pharmacology Toxicology and Pharmaceutics Rats Wistar Fluorescein isothiocyanate Kidney General Medicine Androgen Anti-Bacterial Agents Rats Androgen receptor Low Density Lipoprotein Receptor-Related Protein-2 030104 developmental biology Endocrinology medicine.anatomical_structure chemistry Receptors Androgen Androgens Kidney Diseases Gentamicins |
| Zdroj: | Life sciences. 251 |
| ISSN: | 1879-0631 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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