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

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Elsakka EGE, Elsisi AM, Mansour OAA, Elsadek BEM, Abd Elaziz AI, Salama SA, Allam S

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

Life Sci. 2020 Jun 15;251:117628. doi: 10.1016/j.lfs.2020.117628. Epub 2020 Apr 2.

PubMed ID

32247620 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Gentamicin	Low-density lipoprotein receptor-related protein 2	Protein	Humans	No	Substrate	Details