RESUMEN
BACKGROUND: Compensatory tubular cell hypertrophy following unilateral nephrectomy is a cell cycle-dependent process. Our previous study showed that treatment of unilaterally nephrectomized rats with the immunomodulator AS101 partially inhibits compensatory hypertrophy of the remaining kidneys through the inhibition of IL-10-induced TGF-beta secretion by mesangial cells. The present study is focused on understanding the intracellular mechanism(s) of this phenomenon. METHODS: A total of 120 male Sprague-Dawley rats were unilaterally nephrectomized or sham-operated and treated with AS101 or PBS. Kidney weight and protein/DNA ratio were assessed for each experimental animal. The expression of TGF-beta, PCNA, CDK 2, pRb, ppRb, p21(Waf1), p27(kip1) and p57(kip2) proteins in renal tissues was determined by western blot analysis and immunohistochemistry, and the immunoprecipitation of cyclin E complexes was performed. RESULTS: Compensatory renal growth is initiated by proliferation of resident renal cells that precedes hypertrophy. Changes in TGF-beta expression were positively correlated with the amounts of p57(kip2), but not with p21(Waf1) and p27(kip1) expression in the remaining kidneys. Moreover, there was a marked abundance of p57(kip2) but not p21(Waf1) and p27(kip1) binding to the cyclin E complex in PBS-treated unilaterally nephrectomized rats compared to sham-operated animals. Treatment of uninephrectomized rats with AS101 reduced kidney weight and protein/DNA ratio, inhibited TGF-beta and p57(kip2) expression in the remaining kidneys, and decreased the level of p57(kip2) binding to cyclin E complexes. CONCLUSION: These results demonstrate that TGF-beta-induced compensatory tubular cell hypertrophy is regulated in vivo by p57(kip2) but not by the p21(Waf1) and p27(kip1) cyclin kinase inhibitor proteins.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/metabolismo , Etilenos/farmacología , Túbulos Renales/patología , Factor de Crecimiento Transformador beta/metabolismo , Animales , Western Blotting , Células Cultivadas , Ciclina E/metabolismo , Quinasa 2 Dependiente de la Ciclina/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , ADN/metabolismo , Regulación de la Expresión Génica , Hipertrofia , Técnicas para Inmunoenzimas , Inmunoprecipitación , Interleucina-10/metabolismo , Túbulos Renales/metabolismo , Masculino , Nefrectomía , Antígeno Nuclear de Célula en Proliferación/metabolismo , Ratas , Ratas Sprague-Dawley , Proteína de Retinoblastoma/metabolismoRESUMEN
Epididymitis may be acute (symptoms last less than 6 weeks) or chronic (more than 3 months). Acute epididymitis is almost always unilateral. In sexually active men under 35 years of age, acute epididymitis is frequently caused by Chlamydia trachomatis and less frequently by Neisseria gonorrhoeae and is usually associated with overt or subclinical urethritis. Acute epididymitis in older men, children or following urinary tract instrumentation is commonly caused by gram-negative bacilli. The epididymis is sometimes the site of metastatic infection, such as tuberculosis. It is important to differentiate epididymitis from other causes for acute scrotum, such as testicular torsion and tumor. The cause of acute scrotum especially in children cannot always be identified. Therefore, Doppler ultrasonography and radionuclide scans are often used. In infants and young boys, genitourinary abnormalities are causative factors, and therefore should be excluded by imaging. Supportive measures and antimicrobial agents are the mainstay of therapy.
Asunto(s)
Epididimitis/fisiopatología , Enfermedad Aguda , Adulto , Infecciones por Chlamydia/complicaciones , Diagnóstico Diferencial , Epididimitis/diagnóstico , Epididimitis/etiología , Lateralidad Funcional , Humanos , Masculino , Sífilis/complicaciones , Uretritis/complicacionesRESUMEN
The present study investigated the role of IL-10 produced by the mesangial cells in postnephrectomy compensatory renal growth and the effect of the immunomodulator AS101 on this process. One hundred forty unilateral nephrectomized and sham-operated male Sprague-Dawley rats were treated by AS101 or PBS before and after surgery. The results show that secretion of IL-10 and TGF-beta by mesangial cells isolated from the remaining kidneys was increased significantly, compared with those of control and sham animals. Moreover, TGF-beta secretion by mesangial cells was increased after the addition of exogenous recombinant IL-10 and inhibited in the presence of neutralizing anti-IL-10 antibodies. In vivo, compensatory growth of the remaining kidneys was associated with significant increase in IL-10 content in renal tissues and plasma. Immunohistochemical studies show that IL-10 was produced by mesangial cells. Elevated IL-10 levels were followed by the rise in TGF-beta content in plasma and renal tissue. AS101 treatment decreased IL-10 and TGF-beta expression in plasma and kidney tissues and results in 25% reduction in the fresh and fractional kidney weight and decreased hypertrophy of tubular cells (protein/DNA ratio, morphometric analysis). Taken together, these data demonstrate that TGF-beta production by mesangial cells is IL-10 dependent. Mesangial cells are the major source of IL-10 in kidneys. AS101, by inhibiting the activity of IL-10, decreases TGF-beta production by mesangial cells, thus limiting compensatory tubular cell hypertrophy.