Nefropatia crônica por ciclosporina : papel do ácido úrico e do sistema renina angiotensina aldosterona como mediadores de disfunção endotelial, inflamação e vasculopatia / Cyclosporine nephropathy : effect of uric acid and the renin angiotensin aldosterone system as mediators of endothelial dysfunction, inflammation vasculopathy

Fernanda Cristina Mazali

Chronic allograft nephropathy is characterized by stripped tubular atrophy and interstitial fibrosis, in presence of arteriolar hyalinosis, resembling an ischemic pattern of chronic kidney disease. Chronic ischemia is associated with reduced glomerular filtration rate, and increase in serum uric acid levels. Cyclosporine per se also has a direct effect on tubular urate handling that facilitates the development of hyperuricemia. Hyperuricemia exacerbates chronic cyclosporine nephropathy, with a more severe tubulointerstitial fibrosis and atrophy, as well as worsening of arteriolar hyalinosis. In a previous study we have shown that concomitant treatment with uric acid lowering agents limits the development of experimental CsA nephropathy. The hypothesis of the present study was that treatment with uric acid lowering agents, after the development of CsA nephropathy could reverse or reduce the severity of tubulointerstitial disease. Male Sprague Dawley rats received daily SC injections of cyclosporine in presence of low salt diet, during 5 weeks. At the end of this period, experimental groups were assigned for CsA withdrawal, maintenance of daily CsA alone or associated with allopurinol or benzbromarone in drinking water for an additional period of 4 weeks. At the end of 9 weeks of study, rats were sacrificed for functional and morphological analysis of kidneys. In this model, concomitant treatment with allopurinol or benzbromaroes was associated with reduction of serum uric acid levels, improvement in renal function and renal disease, characterized by lower arteriolar hyalinosis index, less glomerulosclerosis and significant reduction in interstitial fibrosis area. Other findings included reduction in oxidative stress markers and apoptotic cells, despite of maintenance of inflammatory status, quantified by macrophage infiltration and osteopontin expression. Allopurinol treatment was associated with more significant changes, with reduction of free radical generation, and lower grade of apoptotic cells in renal cortex, suggesting a participation of antioxidant effects in association with uric acid reduction. Taken together, these datsa suggests that reduction of serum uric acid in the stablished model of CsA nephropathy has a protective effect in microvascular lesions and progression of interstitial disease, despite the maintenance of interstitial inflammation. In cyclosporine nephropathy, as well as in the experimental hyperuricemia model, renal disease is associated with increased renin activity, suggesting the participation of renin angiotensin aldosterone system (RAS) in the mechanism of disease. In order to analyze the effect of RAS in CsA nephropathy model, a second study tested the treatment with angiotensin converting enzyme inhibitor (enalapril), a angiotensin II AT1 receptor blocker (losartan) or an aldosterone inhibitor (espironolactone) in association with cyclosporine after the development of chronic nephropathy. Experimental animals were treated with cyclosporine and low salt diet for 5 weeks, and then assigned for one treatment group, including cyclosporine withdrawal, cyclosporine alone, CsA and enalapril, CsA and losartan or CsA and espironolactone for an additional period of 4 weeks. RAS blockade in the established model of CsA nephropathy was associated with improvement in renal function and interstitial fibrosis, despite the maintenance of interstitial inflammation. The most striking finding was the improvement of arteriolar hyalinosis and glomerulosclerosis, suggesting that the most important effect was protecting against vascular remodeling. The improvement in vasculopathy was associated with reduction in tissue hypoxia, with a partial reduction in oxidative stress and tubular cell apoptosis. Both therapeutic interventions proved to be efficient in limiting progression of renal disease, with a partial reversion of interstitial fibrosis. The main mechanism is associated with improvement in renal tissue O2 delivery, as a consequence of recovery of arteriolar hyalinosis and control of vascular remodeling. However, maintenance of CsA therapy was associated with a persistent toxic effect, with maintained interstitial inflammation, free radical generation and tubular cell apoptosis that was not neutralized by intervention.

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