| Background and objective Since its introduction in 1976, cyclosporine A (CsA) has lead to a signifiant reduction in acute allograft rejection and improvement in allograft and patient surivial. Cyclosporine A has markedly improved the success rate of solid organ transplantation. Disappointingly, advance in improving short-term renal allograft survival have not translated into enhanced long-term graft function. Chronic CsA nephrotoxicity still remains an important cause of late kidney transplant loss. Long-term CsA immunosuppressive therapy in allograft recipient and in patients with autoimmune diseases has been limited due to the concomitant development of chronic nephrotoxicity, which may progress to an irreversible renal lesion characterized by derangement of renal function and architecture, which is characterized by striped interstitial fibrosis, tubular atrophy, and hyalinosis of the afferent arterioles. In the past, the lack of an animal model of chronic CsA nephrotoxicity has hampered the study of its pathogenesis. Initial success with a rat model of CsA nephrotoxicity was reported by Rosen et al in 1990. In this model, CsA treatment in rats on a low sodium diet induced physiologic and histologic featuresthat resemble the human lesion described in patients on long-term CsA therapy. Experimental models of CsA and renal studies in non-renal transplant patient (bone narrow, liver, heart and lung transplantation) have shed new light on the understanding of function and structure abnormalities of cyclosporine-induced nephropathy.The pathogenesis of chornic cyclosporine-induced nephrotoxicity is multifactorial Both in vivo and in vitro studies indicate that enhanced vasoconstrictor factor release , particularty the activation of the renin-angiotensin-aldosterone system(RAAS)and increased expression of TGF-betal are the predominant factors in the pathogenensis of chronic cyclosporine-induced nephrotoxicity. The increase in this profibrotic cytokine, TGF- P i results in activation of extracellalar matrix protein synthesis, such as collagen and fibronectin(FN), which are known to be associated with the development of interstitial fibrosis.Considerable attention has been directed to angiotensin II (Ang II) as a mediator of renal damage progression observed in several nephropathy, including chronic CsA toxicity. Although aldosterone is part of the renin-angiotensin-aldosterone axis, little attention has been addressed to this mineralocorticoid as a potential key molecule mediating renal damage. Recent studies suggest that aldosterone could play an important role in the progression of renal disease. Continuous infusion of aldosterone in normal rats induced up-regulation of TGF- P imRNA in the kidney.Utilizing the chronic CsA nephrotoxicity model in the rat that was produced by the administration of CsA and a low sodium diet. Our present study investigated spironolactone treatment on renal dysfunction and structural alteration induced by CsA, and evaluated the role of aldosterone in the pathogenesis, and assessed whether administration of spironolactone was associated with the reduction of up-regulation of TGF- 1 and the change of extracellular matrix protein.[Methods] 36 normal male Sprague-Dawley rats, weighting 200-250g, recived a low-salt died (0.037%, sodium). After 1 week, the rats were divided into three groups at random. Control group(n=12); CsA group(n=12): rats received a daily subcutaneous injection of CsA,15mg/kg (CsA was diluted in N.S to a fmial concentration of 10mg/ml); CsA+SPIR group (n-12): rats received CsA and spironolactone, 20mg/kg.d (spironolactone was diluted in sterile water to a fmial concentration of 4mg/ml) by gastric gavage. Six rats from each group were studied at both 2 and 4 weeks. At the end of each 2 or 4 weeks treatment period, systolic blood pressure was measure by a non-invasive tail cuff method The rats were placed in metabolic cages and 24 hours urine were collected and determined the urinary protein excretion . Potasium levels serum and urine creatinine concentration w...
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