RESUMEN
Kidney toxicity accounts both for the failure of many drug candidates as well as considerable patient morbidity. Whereas histopathology remains the gold standard for nephrotoxicity in animal systems, serum creatinine (SCr) and blood urea nitrogen (BUN) are the primary options for monitoring kidney dysfunction in humans. The transmembrane tubular protein kidney injury molecule-1 (Kim-1) was previously reported to be markedly induced in response to renal injury. Owing to the poor sensitivity and specificity of SCr and BUN, we used rat toxicology studies to compare the diagnostic performance of urinary Kim-1 to BUN, SCr and urinary N-acetyl-beta-D-glucosaminidase (NAG) as predictors of kidney tubular damage scored by histopathology. Kim-1 outperforms SCr, BUN and urinary NAG in multiple rat models of kidney injury. Urinary Kim-1 measurements may facilitate sensitive, specific and accurate prediction of human nephrotoxicity in preclinical drug screens. This should enable early identification and elimination of compounds that are potentially nephrotoxic.
Asunto(s)
Biomarcadores Farmacológicos/orina , Moléculas de Adhesión Celular/orina , Pruebas de Función Renal/métodos , Riñón , Acetilglucosaminidasa/orina , Animales , Biomarcadores Farmacológicos/metabolismo , Nitrógeno de la Urea Sanguínea , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Cisplatino/toxicidad , Creatinina/sangre , Ciclosporina/toxicidad , Evaluación Preclínica de Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Gentamicinas/toxicidad , Histocitoquímica , Riñón/efectos de los fármacos , Riñón/lesiones , Pruebas de Función Renal/normas , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Curva ROC , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Daño por Reperfusión , Tioacetamida/toxicidadRESUMEN
BACKGROUND: Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is expressed in the heart and regulates genes involved in myocardial fatty acid oxidation (FAO). The role of PPAR-alpha in acute ischemia/reperfusion myocardial injury remains unclear. METHODS AND RESULTS: The coronary arteries of male mice were ligated for 30 minutes. After reperfusion for 24 hours, ischemic and infarct sizes were determined. A highly selective and potent PPAR-alpha agonist, GW7647, was administered by mouth for 2 days, and the third dose was given 1 hour before ischemia. GW7647 at 1 and 3 mg x kg(-1) x d(-1) reduced infarct size by 28% and 35%, respectively (P<0.01), and myocardial contractile dysfunction was also improved. Cardioprotection by GW7647 was completely abolished in PPAR-alpha-null mice. Ischemia/reperfusion downregulated mRNA expression of cardiac PPAR-alpha and FAO enzyme genes, decreased myocardial FAO enzyme activity and in vivo cardiac fat oxidation, and increased serum levels of free fatty acids. All of these changes were reversed by GW7647. Moreover, GW7647 attenuated ischemia/reperfusion-induced release of multiple proinflammatory cytokines and inhibited neutrophil accumulation and myocardial expression of matrix metalloproteinases-9 and -2. Furthermore, GW7647 inhibited nuclear factor-kappaB activation in the heart, accompanied by enhanced levels of inhibitor-kappaBalpha. CONCLUSIONS: Activation of PPAR-alpha protected the heart from reperfusion injury. This cardioprotection might be mediated through metabolic and antiinflammatory mechanisms. This novel effect of the PPAR-alpha agonist could provide an added benefit to patients treated with PPAR-alpha activators for dyslipidemia.