The role of NFkB in calcineurin inhibitor-induced renal fibrosis

项目摘要/摘要 钙调神经磷酸酶抑制剂(CNI)，如CsA和他克莫司，是治疗糖尿病的重要免疫抑制药物 炎症状态的处理，如移植后免疫抑制、狼疮性肾炎46和 罕见的特应性皮炎47。尽管CNI极大地提高了患者护理的质量，但长期的 治疗会以肾纤维化的形式对肾脏造成不可逆转的损害。这些形态变化 最终导致肾功能下降，并可能进展为终末期肾功能衰竭，这是双方都担心的问题 临床医生和患者。因此，CNI导致肾脏损害的分子机制需要进一步研究 更好地理解，而且到目前为止，还没有具体的治疗策略来减轻这种伤害。 因此，迫切需要解释CNI促进肾损害的机制。 有趣的是，体内cnAα活性的丧失会增加肾脏损伤的标志，如转化生长因子β和 纤维连接蛋白3。目前尚不清楚哪些信号介质促进了肾脏损伤的表达。 Cnaα亚型丢失后的标记。初步数据显示，独家失去央视α不仅促进 肾纤维化标志物的表达还可诱导NF-κ-B活化。然而，下一个问题， 确定这些信号变化是否通过共同的途径发生，目前还没有答案。这 格兰特提案将解决这一认识上的差距，并检验肾脏cnAα抑制的假设 上调核因子κB信号，促进不可逆转的肾损伤。预期的项目成果 将表征中央通讯社α的S通过其对NFκB的调节而在介导肾损伤中的作用。这些发现将 倡导和启发CNA-α节约型CNI的未来发展，最终绕过肾毒性 注意到长期使用CNI。 为此，本提案旨在：1)确定核因子κB激活是否促进肾损害 CNAα抑制和ii)确定肾cNAα抑制如何驱动NFκB信号转导。圆满完成 拟议的工作将确定CNIs肾毒性作用的关键机制，从而为未来提供信息 开发cnA-α节约型CNI和/或额外的治疗方法来对抗这些毒性效应。长期目标 将减轻接受长期CNI治疗的患者的肾脏损害和功能障碍。

Project Abstract/Summary Calcineurin inhibitors (CNIs) such as CsA and tacrolimus are vital immunosuppressive therapies in the management of inflammatory conditions such as post-transplantation immunosuppression, lupus nephritis46 and rare cases of atopic dermatitis47. Although CNIs have dramatically improved the quality of patient care, long-term therapy causes irreversible damage to the kidneys in the form of renal fibrosis. These morphologic changes ultimately lead to a decline in renal function and can progress to end-stage renal failure, a concern for both clinicians and patients. Therefore, the molecular mechanisms by which CNIs induce kidney damage need to be better understood, and to date, there are no specific therapeutic strategies to mitigate this injury. There exists therefore, a critical need to explain mechanisms by which CNIs promote renal damage. Interestingly, loss of CnAα activity in vivo increases markers of renal damage such as TGFβ and fibronectin3. It is currently unknown which signaling mediators promote the expression of renal damage markers upon loss of the CnAα isoform. Preliminary data show that exclusive loss of CnAα not only promotes expression of renal profibrotic markers but also induces NFκB activation. However, the next question, identifying whether these signaling changes occur via a common pathway, has not yet been answered. This grant proposal will address this gap in knowledge and test the hypothesis that renal CnAα inhibition upregulates NFκB signaling, which promotes irreversible renal damage. The expected project outcomes will characterize CnAα’s role in mediating renal damage through its regulation of NFκB. These findings will advocate and inspire future development of CnAα-sparing CNIs, ultimately circumventing the nephrotoxicity noted with long-term CNI use. To this end, this proposal seeks to I) determine whether NFκB activation promotes renal damage upon CnAα inhibition and II) determine how renal CnAα inhibition drives NFκB signaling. Successful completion of the proposed work will identify key mechanisms underlying the nephrotoxic effects of CNIs, thus informing future development of CnAα-sparing CNIs and/or additional therapies to counter these toxic effects. The long-term goal will be to mitigate the renal damage and dysfunction noted in patients placed on long-term CNI therapy.