RESUMO
BACKGROUND: Transforming growth factor-beta (TGF-beta) plays an important role in progression of renal injury. However, few materials which inhibit TGF-beta have been known. Roxithromycin (ROX), macrolide antibiotics, is known to have anti-inflammatory, immunomodulatory and tissue reparative effects besides its bacteriostatic activity, although the exact mechanism of its anti-inflammatory and immunomodulatory effects was not defined. We examined the effect of ROX on production of TGF-beta and type IV collagen by cultured human mesangial cells (HMC). METHODS: Human mesangial cells were incubated with several concentrations of ROX and TGF-beta and type IV collagen levels in the culture supernatants were measured by enzyme-linked immunoassay. Amount of TGF-beta mRNA was also quantified by using a colourimetric mRNA quantification kit and semiquantitative reverse transcriptase polymerase chain reaction. We also examined the effect of ROX on tyrosine kinase, MAP kinase and NF-kappaB stimulated by thrombin. RESULTS: Roxithromycin (0.1-10.0 microg/mL) inhibited TGF-beta production by HMC in a dose- and time-dependent manner without inducing cell injury. ROX (10.0 microg/mL) also inhibited mRNA expression of TGF-beta in HMC. Thrombin (5 U/mL) stimulated TGF-beta production by HMC and ROX significantly inhibited the stimulating effect of thrombin on TGF-beta production. ROX also inhibited the increment of type IV collagen production stimulated by thrombin. ROX (10.0 microg/mL) suppressed the thrombin-induced NF-kappaB activation, although ROX did not inhibit the activation of tyrosine kinase and MAP kinase by thrombin. CONCLUSION: Roxithromycin has an inhibitory effect on TGF-beta production by HMC possibly via inhibition of NF-kappaB. ROX may be a potential agent for the treatment of glomerulosclerosis.
Assuntos
Antibacterianos/farmacologia , Células Mesangiais/efeitos dos fármacos , Roxitromicina/farmacologia , Fator de Crescimento Transformador beta/genética , Células Cultivadas , Colágeno Tipo IV/genética , Colágeno Tipo IV/metabolismo , Interações Medicamentosas , Ativação Enzimática/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Hemostáticos/farmacologia , Humanos , Células Mesangiais/citologia , Células Mesangiais/fisiologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Proteínas Tirosina Quinases/metabolismo , RNA Mensageiro/metabolismo , Trombina/farmacologia , Fator de Crescimento Transformador beta/metabolismoRESUMO
Eicosapentaenoic acid (EPA) is one of the major components of fish oil, which was reported to have antiatherogenic, anti-inflammatory and immune suppressive effects. In the present study, highly purified EPA was administered to patients with lupus nephritis and the effects of EPA on urinary 8-isoprostane, a reliable marker of oxidative stress, were investigated in these patients. Six outpatients (1 man and 5 women), with lupus nephritis diagnosed by renal biopsy, were entered in the study. We administered 1800 mg EPA ethyl-ester (purity > 95%) daily and examined the urinary 8-isoprostane levels and plasma fatty acid composition before and 3 months after EPA treatment. The urinary 8-isoprostane levels were significantly decreased after the treatment compared with those before the treatment (from 530 +/- 113 pg/mg x Cr to 235 +/- 49 pg/mg x Cr, p = 0.02). The EPA levels in the plasma phospholipid (PL) fraction were significantly increased after the treatment (from 3.30 +/- 0.64 mol% to 8.01 +/- 0.47 mol%, p < 0.001). Arachidonic acid (AA) levels in the plasma PL fraction were significantly decreased after the treatment (from 9.47 +/- 0.28 mol% to 7.33 +/- 0.43 mol%, p < 0.001). The ratios of EPA to AA were significantly increased after the treatment (from 0.35 +/- 0.07 to 1.14 +/- 0.16, p < 0.001). Thus, this preliminary study indicated that EPA might exert beneficial effects on lupus nephritis by decreasing the oxidative stress.
