RESUMEN
Clusterin, a protein associated with cell death, has been suggested as a marker of renal injury. Correlation of clusterin gene expression with changes in renal function and quantitative measurement of clusterin protein levels after ureteral obstruction have not been previously reported. With unilateral ureteral obstruction in rabbits as the experimental model, the time course of alterations in renal function, clusterin mRNA accumulation, and concentrations of clusterin protein in serum, urine, and renal tissue were investigated. RBF, GFR, and renal concentrating ability (percent sodium reabsorption and urine osmolarity) all decreased (P < 0.05) in the obstructed kidney from control values within 1 day of ureteral obstruction. Clusterin mRNA levels started to rise in the ipsilateral kidney within 12 h of ureteral obstruction and increased up to 10-fold above control levels after 3 days of obstruction. Hybridization histochemistry showed that clusterin mRNA was initially detectable in collecting ducts and distal tubules within 12 h of ureteral obstruction. After 7 days of obstruction, increased accumulation of clusterin mRNA was also detectable in proximal tubular epithelial cells. Clusterin gene expression remained elevated in collecting ducts after 60 days of obstruction. Clusterin expression in the contralateral kidney was increased twofold over control values after 12 h of obstruction. No increase in clusterin mRNA accumulation was detectable after 24 h in the contralateral kidney. Total clusterin protein in the obstructed kidney increased from 0.59 +/- 0.66 (mean +/- 1 SD) to 2.5 +/- 1.3 micrograms after 7 days of ureteral obstruction (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Glicoproteínas/biosíntesis , Chaperonas Moleculares , Obstrucción Ureteral/metabolismo , Animales , Secuencia de Bases , Muerte Celular , Clusterina , Expresión Génica , Tasa de Filtración Glomerular , Hibridación in Situ , Riñón/metabolismo , Riñón/fisiopatología , Masculino , Datos de Secuencia Molecular , Natriuresis , ARN Mensajero/análisis , Conejos , Circulación RenalRESUMEN
Measurements of tissue immunoassayable clusterin, a protein associated with programmed cell death and tissue reorganization, were performed in rats treated with nephrotoxic doses of gentamicin sulfate. Adult Lewis rats were treated with 100 mg/kg/day of gentamicin sulfate for 12 days. Urine, serum, and tissue levels of clusterin protein were measured, as were urinary N-acetyl beta-glucosaminidase (NAG) and serum creatinine levels. Induction of renal injury by gentamicin was detectable within 4 days by increased levels of urinary N-acetyl beta-glucosaminidase (from 280 +/- 66 (mean +/- SD) to 910 +/- 210 nmol/mg creatinine), and within 9 days of initiating gentamicin treatment by increased serum creatinine (from 0.5 +/- 0.1 to 1.2 +/- 0.4 mg/dl). Paralleling these changes, renal, urinary, and serum levels of clusterin increased 10-, 116-, and 3-fold (P less than 0.05). Treatment with gentamicin sulfate did not increase clusterin levels in the seminal vesicle, ventral prostate, testis, or epididymis. The measurement of urinary or serum clusterin may play a role in the early detection of renal injury.
Asunto(s)
Gentamicinas/toxicidad , Glicoproteínas/orina , Riñón/patología , Chaperonas Moleculares , Acetilglucosaminidasa/orina , Animales , Biomarcadores/sangre , Biomarcadores/orina , Clusterina , Creatinina/orina , Citosol/química , Epidídimo/efectos de los fármacos , Epidídimo/fisiología , Glicoproteínas/análisis , Glicoproteínas/sangre , Riñón/efectos de los fármacos , Riñón/fisiología , Hígado/efectos de los fármacos , Hígado/fisiología , Masculino , Próstata/efectos de los fármacos , Próstata/fisiología , Radioinmunoensayo , Ratas , Ratas Endogámicas Lew , Vesículas Seminales/efectos de los fármacos , Vesículas Seminales/fisiología , Testículo/efectos de los fármacos , Testículo/fisiologíaRESUMEN
STUDY OBJECTIVE: 1) to investigate serum levels of tumor necrosis factor-alpha in patients treated with recombinant interferon-gamma and 2) to relate changes in TNF serum levels to other biological responses observed during treatment with interferon gamma (IFN-gamma). PATIENTS: Five patients suffering from metastasizing renal cell carcinoma. INTERVENTION: Each patient received three treatment cycles of 10 micrograms, 100 micrograms and 500 micrograms IFN-gamma applied three times at weekly intervals. The treatment cycles were separated by a therapy free interval of two weeks. The order of dose levels was randomly assigned to each patient. MEASUREMENTS AND MAIN RESULTS: Tumor necrosis factor alpha (TNF-alpha), IFN-gamma and neopterin serum levels, monocyte counts in the peripheral blood and body temperature were measured immediately before and 4, 24, 48, 72, and 168 h after each application of IFN-gamma. Results indicated that elevated serum levels of TNF-alpha are induced by 100 micrograms and 500 micrograms IFN-gamma. Repeated application of the same dose led to downregulation of TNF release into the serum. Changes in TNF serum levels did not correlate with the magnitude of febrile reactions, neopterin production or IFN-gamma serum levels.