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

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.

journal_name

Life Sci

journal_title

Life sciences

authors

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

doi

10.1016/j.lfs.2020.117628

subject

Has Abstract

pub_date

2020-06-15 00:00:00

pages

117628

eissn

0024-3205

issn

1879-0631

pii

S0024-3205(20)30376-3

journal_volume

251

pub_type

杂志文章

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