Steroid therapy and urinary transforming growth factor-beta1 in IgA nephropathy.

Transforming growth factor-beta1 (TGF-beta1) has an important role in the pathogenesis of glomerular damage by influencing matrix metabolism. An association of TGF-beta1 with glomerulosclerosis and interstitial fibrosis has been shown in various renal diseases, suggesting that TGF-beta1 may serve as a diagnostic marker of glomerular diseases. The aim of this study is to determine the usefulness of urinary TGF-beta1 values to monitor therapeutic effects of steroids in patients with immunoglobulin A (IgA) nephropathy. Concentrations and activation rates of TGF-beta1 (mature/total) were determined in urine of patients with renal diseases by means of a double-antibody enzyme immunoassay. The urinary TGF-beta1 level before steroid therapy was compared with renal histological characteristics, creatinine clearance, and proteinuria in patients with a variety of renal diseases. Urinary excretion of total and mature TGF-beta1 was significantly greater in patients with crescentic glomerulonephritis and IgA nephropathy than in healthy controls, whereas the activation rate of urinary TGF-beta1 was similar among patients with other renal diseases. Urinary TGF-beta1 excretion at the time of renal biopsy significantly correlated with the degree of crescent formation in patients with IgA nephropathy, but not in those with glomerular sclerosis or tubulointerstitial fibrosis. Urinary excretion of total and mature TGF-beta1 was reduced in patients with IgA nephropathy after treatment with prednisolone (0.8 mg/kg/d) for 1 month. The activation rate of urinary TGF-beta1 also decreased significantly after steroid therapy. Urinary TGF-beta1 values therefore may be useful to assess disease activity or the effects of steroid therapy in patients with IgA nephropathy.

Long-term smoking causes nitroglycerin resistance in platelets by depletion of intraplatelet glutathione.

We investigated whether platelet responsiveness to nitroglycerin (NTG) is maintained in long-term smokers and if not, the mechanism. In the absence or presence of NTG, intraplatelet reduced glutathione (GSH) levels and ADP-induced platelet aggregation and intraplatelet cGMP levels were measured in 10 long-term smokers and 10 age-matched nonsmokers. The intraplatelet GSH level was significantly lower in smokers than in nonsmokers (P<0.05). Platelet aggregation was dose-dependently inhibited by NTG in both groups; however, inhibition was significantly weaker in smokers. N-acetylcysteine (1 mmol/L), an exogenous thiol agent, significantly potentiated NTG-induced platelet inhibition in nonsmokers but not in smokers. The ADP-induced intraplatelet cGMP level was significantly greater in the presence of NTG in nonsmokers but not so in smokers. Because the effects of long-term smoking are multifactorial, a rabbit model was made by chronic administration of buthionine sulfoximine (BSO, n=6) to decrease intraplatelet GSH. The intraplatelet GSH level was significantly lower in BSO-treated rabbits than in saline-treated rabbits (P<0.001). The NTG-induced inhibition of platelet aggregation was significantly weaker in BSO rabbits. N-acetylcysteine-induced potentiation was not observed in BSO rabbits, whereas significant potentiation was found in saline rabbits. These findings were similar to those of long-term smokers. In contrast, the intraplatelet GSH-to-oxidized glutathione ratio, which represents the redox state of glutathione, was significantly lower in smokers than in nonsmokers, whereas no difference was found between saline rabbits and BSO rabbits. In conclusion, long-term smoking causes NTG resistance to aggregation in platelets, possibly through the depletion of intraplatelet GSH.