Synergistic protective effects of mizoribine and angiotensin II receptor blockade on cyclosporine A nephropathy in rats

Abstract

BACKGROUND:Chronic cyclosporine A (CsA) nephrotoxicity is manifested by renal dysfunction, progressive histopathological kidney lesions characterized by afferent arteriolopathy, and tubulointerstitial fibrosis. In addition to the direct toxic effect of CsA, many other etiological factors such as angiotensin II, transforming growth factor (TGF)-β, and macrophage infiltration are involved in this pathogenesis. This study investigated the hypothesis that concomitant administration of mizoribine (MZR) and angiotensin II receptor blockade (ARB) may prevent CsA nephrotoxicity in rats. MethODs: Sprague-Dawley male rats were divided into the following seven groups: group 1, treated with CsA; group 2, treated with CsA + MZR; group 3, treated with CsA + valsartan (Val); group 4, treated with CsA + MZR + Val; group 5, treated with MZR; group 6, treated with Val; and group 7, controls (n = 5 each). Renal histopathology and the effect of CsA-induced nephrotoxicity on inflammatory mediators were evaluated. ResUlts:Results of this study demonstrated that ARB administration significantly decreased arteriolopathy and that in comparison with monotherapy, concomitant administration of MZR and ARB further decreased arteriolopathy, fibrosis, macrophage infiltration, and TGF-β1 mRNA expression associated with CsA nephrotoxicity. CONClUsiON: These findings indicate that MZR and ARB combination treatment provides synergistic protective effects against chronic CsA nephrotoxicity. C yclosporine A (CsA), a fungal cyclic polypeptide, is an immunosuppressant widely used in cases of organ transplantation and autoimmune diseases. CsA administration has been extended to the treatment of nephrotic syndrome in children, particularly in those with steroid dependency and resistant nephrotic syndrome due to steroid toxicity (1). However, the therapeutic benefits of CsA are often limited by chronic nephrotoxicity developing from long-term use of this drug. Chronic CsA nephrotoxicity is manifested by renal dysfunction and progressive histopathological kidney lesions characterized by afferent arteriolopathy, tubular vacuolization, tubular atrophy, and interstitial fibrosis (2).Mizoribine (MZR) is a purine nucleotide analog isolated from Eupenicillium brefeldianum (3) and has been clinically used as an immunosuppressant following renal transplantation and for lupus nephritis and for nephrotic syndrome. Recent studies have demonstrated that MZR suppresses infiltration of macrophages, which play an important role in the development of interstitial fibrosis and obstructive nephropathy in rats and proliferation of rat glomerular epithelial cells (4,5). Recent reports stated that concomitant administration of MZR significantly improved CsA-induced interstitial fibrosis and macrophage infiltration in CsA-treated rats. However, no decrease in arteriolopathy or expression of transforming growth factor (TGF)-β1 was observed after additional MZR administration in a model of CsA nephropathy (6).On the other hand, activation of the renin-angiotensin-aldosterone sy...

Influence of cyclosporine A on glomerular growth and the effect of mizoribine and losartan on cyclosporine nephrotoxicity in young rats

“…In our study, we selected the MZR and LSRT for the potential drugs whether these drugs could prevent acute and chronic CsA nephrotoxicity based on previous studies 12 13 . MZR is extracted from the Eupenicillium brefeldianum as a purine nucleotide analog 29 , and has been used in the treatment of lupus nephritis and nephrotic syndrome 30 .…”

“…However, previous researches have not investigated whether the MZR or LSRT might have a beneficial effect on glomerular growth 12 13 , which could be decreased by CsA. We thought that measurement of glomerular growth will be important because long-term use of CsA is also inevitable in some children as well as in adults and a younger age at the start of CsA is known to be one of the important factor for the development of chronic CsA nephrotoxicity in children with nephrotic syndrome 8 .…”

“…There have been some studies on the protective effects of various drugs such as mycophenolate mofetil, mizoribine and RAS blocekrs on chronic CsA nephrotoxicity in animals 11 12 13 . However, there has been no report on the effect of these drugs on acute or chronic CsA nephrotoxicity regarding glomerular growth in young rats.…”

The inflammatory state provokes sexual dimorphism in left ventricular and electrocardiographic effects of chronic cyclosporine in rats

“…Nuclear factor kappa B (NFκB) is one of the most important key genes in controlling cellular inflammation and redox production 9 and one of the most important mediators of CSA effects 10 . The activation of the renin-angiotensin system (RAS) and angiotensin AT 1 receptors is predisposed to cardiac cellular oxidative stress generation 11 and the blockade of these receptors protects against CSA nephrotoxicity 12 . On the other hand, adipokines such as adiponectin inhibit cellular inflammation and oxidative stress 13 .…”