The protective role of estrogen and its receptors in gentamicin-induced acute kidney injury in rats
Introduction
Gentamicin, one of the aminoglycoside antibiotics is highly effective in the treatment of severe gram-negative infections which are resistant to other antibiotics [1]. Single daily dose of 160 mg of gentamicin is effective in the treatment of urinary tract infections [2]. Unfortunately, the clinical use of this antibiotic is limited due to its nephrotoxicity mostly on the epithelial cells of the proximal tubules [3].
Megalin, a multi-ligand endocytic receptor, belonging to the low-density lipoprotein receptor family [4], is widely expressed in epithelial cells of the proximal tubules [5]. The uptake of aminoglycosides into the kidney in mice lacking megalin is eliminated and directly correlates with renal megalin expression/functionality; providing unequivocal evidence, that megalin is the only major pathway responsible for the renal accumulation of aminoglycosides and representing a unique target to prevent aminoglycoside-induced nephrotoxicity [6]. Given the indispensable endocytic and renal uptake role of megalin to aminoglycosides, it is rational to anticipate that modulation of this receptor expression/endocytic functionality in the epithelial cells of the proximal tubules could modulate gentamicin-induced AKI.
The kidney is a non-reproductive estrogenic organ with specific renal estrogen-induced gene activation. The estrogen receptor α expression in the epithelial cells of the proximal tubules is more pronounced than estrogen receptor – β subtype [7], however, both subtypes are co-expressed with megalin receptor [8,]. The co-localization of estrogen and megalin receptors, suggests that estrogen receptors, which are activated by ligand with 17-β estradiol are involved in regulating megalin expression in the epithelial cells of the proximal tubules. Besides, substantial evidence demonstrated that aminoglycosides exhibit sex-dependent nephrotoxicity, however, the exact molecular mechanisms whereby 17-β estradiol/estrogen receptors exert their effects are still unknown [[11], [12], [10]].
Serum creatinine is considered as delayed and unreliable indicator of acute kidney injury because it is influenced by multiple non-renal factors, such as age, gender, muscle mass, muscle metabolism, diet, and hydration status; it takes several days to reach a new steady-state and not rise until more than half of the kidney function is lost [13]. The blood urea nitrogen is relatively insensitive and unreliable to early kidney deterioration; its level is affected by high catabolic states and high protein diets. Besides, damage to 75% of nephrons is required before increase in its level [14].
Given the limitations of the traditional biomarkers (serum creatinine and blood urea nitrogen) as imprecise markers for acute kidney injury, they are substituted by the more sensitive and reliable biomarkers (kidney injury molecule-1, cystatin C, gamma-glutamyl transferase and lactate dehydrogenase).
Regarding the extremely efficacious effect of gentamicin in critical infections, it is imperative to achieve optimal renoprotective therapy against its nephrotoxicity. Our study aimed to estimate the role of 17-β estradiol/estrogen receptors, estrogen receptor down-regulator (fulvestrant), the phytoestrogen (genistein) and external supplementation of estrogen (estradiol benzoate) in megalin expression/endocytic functionality and consequently their roles in exaggerating or mitigating the gentamicin-induced acute injury.
Section snippets
Animal care and ethical approval
Adult female Wistar albino rats (2 months old, weighing approximately 180–200 g) were purchased from the experimental animal facility at the Nile for Pharmaceuticals & Chemical Industries (Cairo, Egypt). Rats were kept two per cage for two weeks for acclimatization in controlled housing conditions (room temperature 25 ± 2 °C, humidity (50–70%) and 12/12 h dark-light cycles) and kept free on a standard diet. Rats were given ad libitum access to food and water. The study was performed under the
Serum creatinine and BUN assessment
No statistically significant difference was noticed in serum levels of creatinine and BUN in Sham and OVX groups either received or did not receive the scheduled treatment regimen of gentamicin. At the proposed treatment dose level and duration of fulvestrant, genistein and estradiol benzoate, no significant difference in serum levels of creatinine and BUN was estimated between Sham and OVX groups either received or did not receive gentamicin compared to those received fulvestrant, genistein
Discussion
It is believed that gender disparity effects on nephrotoxic drugs could be attributed to the differences in the expression of drug transporters; thus, this sex-related difference in the expression of drug transporters could alter the renal uptake, accumulation, and nephrotoxicant-induced renal injury [31].
Megalin role in gentamicin endocytosis has received much attention. The estimated directly proportional correlation between megalin expression and the serum levels of the novel
Conclusion
The estimated directly proportional relationship between megalin expression and the serum levels of the novel AKI biomarkers, sharply confirmed that megalin is implicated in gentamicin-induced AKI. The protective effect of E2/ERs against gentamicin-induced AKI was clarified by our finding that E2 depletion post-ovariectomy and ERs blocking with fulvestrant elevates renal tissues megalin expression, linked directly with the apparent exaggerated gentamicin-induced AKI. The gentamicin-induced AKI
Declaration of competing interest
The authors declare that there was no conflict of interest.
Acknowledgments
The authors are greatly thankful to Dr. Wagdy Khalil, Professor of Molecular Genetics, Cell Biology Department, National Research Centre (NRC), Dokki, Giza, Egypt for his kind help in ELIZA assay and Dr. Sayed Abdel Raheem, Assistant professor of pathology, Al-Azhar University, Faculty of Medicine, Cairo for his kind help in histopathological investigation.
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