| Background Cyclosporine A (CsA) is a basic immunosuppressant agent in organ transplantation and autoimmune disease. Short-term (ex: 1-year) kidney, heart, liver, lung and pancreas allograft survival rates have been greatly improved since the clinical use of CsA. One-year renal allograft survival rates now approach or surpass 90%, compared to survival rates of 60% or less in the 1980s. Now one-year hepatic allograft survival rates are 70% - 80%, 30% -50% before clinical CsA use. However, the long-term viability of both renal and nonrenal allograft has not shown similar improvement. At present five-year liver allograft survival rates are 60% or less. And calcineurin inhibitor-based immunosuppressant such as CsA and FK506 treatment is associated with a variety of side effects, especially their chronic nephrotoxicity that can shorten the long-term survival rates of patients and allografts. The use of CsA or FK506 in allograft patients of kidney, heart, liver lung, pancreas and autoimmune disease patients produces nephrotoxicity. CsA causes two forms of nephrotoxicity: functional or acute nephrotoxicity and structural or chronic nephrotoxicity. Functional nephrotoxicity is related to the dose of CsA, may be reversible with drug withdraw), is associated with alterations in renal hemodynamics and glomerular filtration rate that begin soon after initiation of CsA treatment, and is largely mediated by an imbalance of vasoconstrictors (endothelin-1, thromboxane A2 (TXA2), angiotensin II, platelet activation factor, et al.) and vasodilators (nitric oxide, prostaglandins). CsA-induced reactive oxygen species (ROS) mediates functional nephrotoxicity. Structural or chronic nephrotoxicity may not be reversible and often isprogressive, involves both the renal arterioles and tubules, and may be mechanistically distinct from functional nephrotoxicity. Structural nephrotoxicity is characterized by afferent arterioles hyalinization, tubular atrophy, striped interstitial fibrosis and glomeruloscerosis. The mechanisms leading to chronic nephrotoxicity of calcineurin inhibitor are unclear. The following factors that are associated with chronic nephrotoxicity: The injured tubular and interstitial cells by CsA express transforming growth factor-pl(TGF-pl), and macrophage chemoattractant and/or adhesion protein such as osteopontin and monocyte chemoattractant protein-1, which promote fibrosis and local inflammatory response.The inhibitory effect of TGF-pl for breakdown of extracellular matrix (ECM) may involve increasing expression of plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of metalloproteinase-l(TIMP-l); Besides their vasocontrictor effects, endothelin-1, TXA2 and leukotriene (LT) also stimulate an increase in protein expression of TGF-pl and ECM. CsA-induced lipid peroxidation causes the production of ROS, TXA2 and LT. Treatment with the TXA2 and LT receptor antagonist could ameliorate the CsA-mediated acute and chronic nephrotoxicity; CsA has also been shown to activate apoptosis genes and increase tubular and interstitial cells apoptosis, and CsA-induced apoptosis correlates with tubular atrophy and tubulointerstitial fibrosis. Namely TGF-pl, macrophage chemoattractant, PAI-1 and TIMP-1, vasocontrictor mediators, and apoptosis are involved in CsA-induced chronic nephrotoxicity.CsA and FK506 are commonly useful in the field of transplantation and belong to calcineurin inhibitor, which disrupts normal intracellular signaling within T-lymphocyte and inhibits the transcription of interleukin-2, tumor necrosis factor-a, granulocyte macrophage colony-stimulating factor and a number of other genes. Their mechanism to activate T-lymphocyte and their clinical side effects are very similar. Nephrotoxicity of CsA and FK506 has been proven to be one of factors that limit the long-term survival rates of both patient and graft.Tea polyphenals (TP) is an extract of green tea, has the low-potential of redox and potent antioxidative effect. TP can neutralize free oxygen radicals such as O2~, OH- in vitro and in...
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