الفهرس | Only 14 pages are availabe for public view |
Abstract Cyclosporine A (CsA) is a potent immunosuppressive agent that is well established for treatment of solid organ transplantation as well as for autoimmune diseases. However, chronic nephrotoxicity is a serious problem that cannot be ignored during therapy. Chronic CsA nephrotoxicity is characterized by intense renal vasoconstriction that often progresses to chronic injury with irreversible structural damage. Although, the exact mechanism of CsA nephrotoxicity remains unclear, experimental evidence suggests an important role of the vasorelaxant mediators in the pathogenesis of the renal vasoconstriction initiating CsA nephrotoxicity, in particular NO. Hence, manipulation of the NO pathway may produce major medical benefits in prevention of CsA-induced nephrotoxicity. CsA causes tubular injury through multiple mechanisms including hypoxia, generation of oxidative stress, inflammation and apoptosis. Although there is a significant correlation between NO level on one hand and oxidative stress, inflammation and apoptosis on the other hand, the pathophysiology of these relationships is not well understood in CsA nephrotoxicity. Sildenafil is a potent vasodilator, which is well stablished to possess an antioxidant, anti-apoptotic and anti-inflammatory properties through NO/cGMP pathway. However, the renoprotective effect of sildenafil in chronic CsA nephrotoxicity is not fully defined. In the present study, a trial was undertaken to investigate the possible role of NO in the incidence of CsA-induced nephrotxicity and to recognize the relationship between NO level on one hand and the produced oxidative stress, apoptosis and inflammation associated with chronic CsA nephrotoxicity on the other hand. Furthermore, the study was extended to find out whether these changes were mediated via modulation of NO pathway or not. In this concern, sildenafil was used alone and in combination with L-NAME in a rat experimental model of chronic CsA nephrotoxicity to evaluate its possible renoprotective effect and the possible mechanism(s)underlying this effect. The study reveals that Prolonged CsA administration resulted in irreversible chronic nephropathy which impedes its clinical use. Moreove, it was found that NO has a potential role in CsA nephrotoxicity as it was observed a strong relation between renal total NOx - level and produced oxidative stress, apoptosis and inflammation in CsA treated rats. Sildenafil administration safely protects against nephrotoxicity associated with CsA treatment and ameliorates renal dysfunction, oxidative stress and inflammation observed in the rat model of CsA nephrotoxicity. Based on these findings observed in the present investigation, it is quite possible to assume that sildenafil holds potential as an adjuvant therapy for protection against CsA nephrotoxicity, although further clinical studied are needed to support this assumption. |