Study of Urinary Biomarkers for Nephrotoxicity in Wistar Rats

Abstract

Urinary biomarkers have been used widely in preclinical toxicity studies to detect dys-functions and injuries of the kidney caused by drugs under development. While they have been well studied for evaluating nephrotoxicity, knowledge of sex differences in excretion levels of urinary biomarkers remains inadequate. We conducted experiments focused on effects of endogenous sex hormones on uri-nary biomarkers using intact and castrated male and female rats. Comparisons of the urinary biomarker excretion levels between intact male and female rats at 5, 7, 9 and 12 weeks of age revealed higher excre-tion levels of leucine aminopeptidase (LAP), γ-glutamyl transpeptidase (γGTP), total protein, liver-type fatty acid-binding protein (L-FABP), cystatin C (Cys-C) and β2-microglobulin (β2-MG), and lower excre-tion level of kidney injury molecule 1 (Kim-1), in male rats as compared to female rats. Orchidectomized male rats showed lower urinary excretion levels of alkaline phosphatase (ALP), LAP, γGTP, N-acetyl-β-D-glucosaminidase (NAG), glucose, total protein, L-FABP, Cys-C, β2-MG and neutrophil gelatinase-associated lipocalin (NGAL), and higher urinary excretion levels of clusterin (CLU) and Kim-1, than sham-operated male rats. On the other hand, no significant differences in the urinary biomarker excre-tion levels excluding ALP were observed between ovariectomized and sham-operated female rats. In the present study, we demonstrated the existence of sex differences in excretion levels of urinary biomarkers that are universally used in preclinical toxicity studies, and also that these differences, especially in relation to the urinary excretions of ALP, LAP, γGTP, total protein, L-FABP, Cys-C, and β2-MG, may closely relate to the endogenous testosterone.

Feasibility of Protein Biomarkers in the Prediction of Subclinical Doxorubicin Nephrotoxicity in Male Sprague-Dawley Rat

“…Doxorubicin related renal injury was associated with elevated uMAlb/uCr (62.5-fold, p=0.05), uTP/uCr (74.3-fold, p=0.05) and uAlb/uCr (>33.1-fold, p=0.05) on day 14. These findings are consistent with previous studies that demonstrated the utility of uTP and uAlb concentrations for monitoring glomerular injury with renal tubule reabsorption impairment in rats and humans [1][2][3][4][5][6][7]. Both uTP and uAlb have been qualified as rat urinary renal biomarkers for the prediction of compound-induced renal dysfunction, tissue injury response and tissue Multi-focal decrease of Bowman's space and mesangial expansion (glomeruli)…”

“…In this study, the feasibility of protein biomarkers in the prediction of subclinical doxorubicin nephrotoxicity was evaluated in male Sprague-Dawley rats [2][3][4][5][6]. Of the doses tested, only the doxorubicin (5 mg/kg/dose) and concurrent control (vehicle) group animals were evaluated for detection of novel renal biomarker concentration changes because higher doses of doxorubicin (7.5 and 10 mg/kg/dose) were associated with clinical signs of systemic toxicity and histopathology findings.…”

Role of Cystatin-C as Serum Biomarkers in Predicting Glomerular Function-Associated with Copper-Induced Acute Kidney Injury

“…4 Cystatin-C is one of many biomarkers that sensitively detect an acute renal function disorders. 5 Cystatin C is a superfamily member of cystatin cysteine protease inhibitors with a molecular weight of 13.3 kDa. Almost all cells that have a nucleus synthesize Cystatin C in a constant amount.…”

Comparison of the therapeutic role of garlic extract and verapamil against gentamicin-induced nephrotoxicity in rats

“…In renal cells, leading to kidney disease, renal hypoxia, and then acute renal failure Perhaps this is what actually happened in the current study, it is also possible that liver tissues are affected by harmful free radicals, and due to reduced levels, the defense system in these tissues loses the ability to clean and process them, reducing glutathione and hydrogen peroxide. Enzymes are produced as a result of their depletion in removing these toxins, providing evidence of hepatotoxicity and nephrotoxicity (23).…”