INVESTIGADORES
MOLINAS Sara Maria
congresos y reuniones científicas
Título:
Enzymuria and HSP-70 urinary excretion in an experimental model of acetaminophen induced nephrotoxicity
Autor/es:
ROSSO, MARINA; MOLINAS, SARA M.; PAGOTTO, MELINA; MONASTEROLO, LILIANA; TRUMPER, LAURA
Lugar:
Milan
Reunión:
Congreso; World Congress of Nephrology 2009; 2009
Institución organizadora:
International Society of Nephrology
Resumen:
INTRODUCTION AND AIMS:Acetaminophen (APAP) is a widely used over-the-counter analgesic and antipyretic drug that is safe at therapeutic dosages. In overdose situation it produces hepatic necrosis and renal failure. In our laboratory, we have reported the development of a reversible model of APAP-induced acute renal failure in male Wistar rats (Arch.Toxicol., 66: 107, 1992).The 70kD heat shock protein (HSP-70) has been associated with cytoprotection in response to several injuries. It has been suggested that HSP-70 inducers would represent a new antidote to APAP induced hepatotoxicity. The aim of this work was to analyze whether HSP-70 is excreted in urine of APAP-intoxicated rats and if this is associated with its renal induction. Other urinary biomarkers of tubular cell integrity as ã glutamyl transpeptidase (ãGT), alkaline phosphatase (AP) and N-acetyl-â glucosaminidase (NAG) were evaluated as early biomarkers of APAP nephrotoxicity.METHODS:Rats were injected i.p. with 750 mg/kg APAP and placed on metabolic cages. Urine was collected after 4 (APAP4), 16 (APAP16); 24 (APAP24); 48 (APAP48) and 96 (APAP96) hs of APAP administration. Except in the APAP4 group, the urine collection period was of 16 hs. After urine collection, rats were anesthetized, and a blood sample was obtained for creatinine and urea measurements. Both kidneys were removed and cortex and medulla were dissected out and homogenized for immunodetection of HSP-70. A group of rats received APAP vehicle (C). n was 4-5 per experimental group.RESULTS:Plasma creatinine and urea levels significantly increased after 16 hs of APAP administration (Creatinine: C= 0.6 ± 0.09, APAP4= 0.8 ± 0.18, APAP16= 1.27 ± 0.18**, APAP24= 1.0 ± 0.13**, APAP48= 0.6 ± 0.28, APAP96= 0.5 ± 0.1 mg/dl; ** p<0.01 versus C). HSP-70 was detected by western blot in the urines of APAP4, APAP16 and APAP24 rats. HSP-70 was significantly increased in the medullas from APAP24 and APAP48 groups. Urinary NAG, ãGT, and AP were increased earlier than creatinine or urea increment (NAG: C= 28.7 ± 3.6, APAP4= 60.6 ± 3.0**, APAP16= 65.82 ± 2.5**, APAP24= 59.8 ± 3.1**, APAP48= 22.6 ± 3.9, APAP96= 22.12 ± 2.5; ãGT: C= 985 ± 149, APAP4= 4417 ± 210**, APAP16= 4636 ± 225**, APAP24= 2008 ± 190**, APAP48= 782 ± 110, APAP96= 903 ± 131, AP: C= 330 ± 97, APAP4= 1055 ± 90**, APAP16= 963 ± 89**, APAP24= 439 ± 97, APAP48= 177 ± 15, APAP96= 183 ± 37, results are expressed as U/ g creatinine, ** p<0.01 versus C).CONCLUSIONS:Our results suggest that tubular enzymuria could be a suitable early biomarker of APAP-induced nephrotoxicity. HSP70 urinary excretion would indicate the loss of tubule integrity as well as its renal induction. HSP inducers could be assayed as potential therapeutic agents against APAP induced nephrotoxicity and HSP-70 induction and the extent of renal damage could be monitored by tubular enzymes and HSP-70 urinary excretion.