The protective role of estrogen and its receptors in gentamicin-induced acute kidney injury in rats

• Published in: Life sciences (1973) Vol. 239; p. 117082
• Main Authors: Abd El-Lateef, Sayed M., El-Sayed, El-Sayed M., Mansour, Ahmed M., Salama, Salama A.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 15-12-2019; Elsevier BV
• Subjects: 17β-Estradiol; Acute Kidney Injury - chemically induced; Acute Kidney Injury - metabolism; Acute Kidney Injury - pathology; Acute Kidney Injury - prevention & control; Animals; Benzoates; Biomarkers; Bovine serum albumin; Correlation; Creatinine; Cystatin C; Epithelial cells; Estradiol - metabolism; Estrogen Receptor beta - metabolism; Estrogen receptors; Estrogen/estrogen receptors; Estrogens; Estrogens - metabolism; Estrogens - physiology; Female; Fluorescence; Fulvestrant; Fulvestrant - metabolism; Genistein; Genistein - pharmacology; Gentamicin; Gentamicins - adverse effects; Gentamicins - pharmacology; Injuries; Isothiocyanate; Kidney - metabolism; Kidneys; L-Lactate dehydrogenase; Lactate dehydrogenase; Lactic acid; Low Density Lipoprotein Receptor-Related Protein-2 - metabolism; Megalin; Nephrotoxicity; Ovariectomy; Phytoestrogens - pharmacology; Proximal tubules; Rats; Rats, Wistar; Receptors; Receptors, Estrogen - metabolism; Receptors, Estrogen - physiology; Rodents; Serum albumin; Serum levels; Sex hormones; Supplements; Surgery; Urea; γ-Glutamyltransferase; Kim-1; IHC; TRE; Gentamicin; E2; AP-1; Megalin; DR; OVX; LDH; LDL; BUN; AKI; PTECs; FITC-BSA; ERs; GPR30; AF1; AF2; Estrogen/estrogen receptors; GGT; SP1; ChIP-seq; ERE; LRP-2; Nephrotoxicity
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2019.117082

Investigating the impact of 17β-Estradiol/estrogen receptors in gentamicin-induced nephrotoxicity.
Three weeks post-ovariectomy or sham surgery for the Wistar albino female rats, thirty sham rats were randomly grouped (n = 6), received either vehicle or gentamicin; the estrogen receptors down regulator (fulvestrant); gentamicin plus fulvestrant; gentamicin plus the phytoestrogen (genistein). Forty–eight ovariectomized rats were randomly grouped (n = 6), treated with either vehicle or gentamicin; fulvestrant; gentamicin plus fulvestrant; genistein; gentamicin plus genistein; estradiol benzoate; gentamicin plus estradiol benzoate. Just post-treatment termination, the traditional kidney injury biomarkers (serum creatinine and blood urea nitrogen) and novel biomarkers (serum Kidney injury molecule −1, cystatin C, lactate dehydrogenase and, gamma-glutamyl transferase) were determined. Bovine serum albumin labeled with fluorescence isothiocyanate assessed megalin expression/endocytic functionality in the proximal tubules epithelial cells (PTECs). The immunohistochemical investigation for the same-sectioned slides of PTECs assessed the correlation between estrogen receptors α and megalin receptors expression. Histopathological examination of PTECs and subjective scoring system graded the damage markers.
Estrogen receptor α expression was markedly dimensioned post-ovariectomy, co-localized and inversely correlated to megalin expression. Serum levels of the novel biomarkers were directly proportional to megalin expression in the PTECs and inversely correlated with estrogen receptor α expression. The injury was exaggerated in ovariectomized and intact rats received fulvestrant. Supplementation with estrogen or genistein ameliorated this injury.
Estrogen/estrogen receptors have a protective impact on gentamicin-induced acute kidney injury. Estrogen receptors antagonist exacerbate the injury, and oppositely, estrogens or phytoestrogens improve it.
•Gentamicin induced acute kidney injury.•Megalin is implicated in gentamicin-endocytosis.•Genistien and estradiol ameliorated gentamicin-induced acute kidney injury.•Fulvestrant exaggerated gentamicin-induced acute kidney injury.