Targeting cell membrane repair for treatment of acute kidney injury

 描述(由申请人提供)：肾近端小管上皮(PTE)的损伤是急性肾损伤(AKI)的根本原因，这些应激反应包括缺血再灌注(I/R)和肾毒素。肾脏细胞具有内在的机制，可以被激活以保护它们在应激条件下的生存。促进PTE细胞的修复将在AKI的治疗中产生有益的效果；然而，在了解与这些细胞损伤修复相关的机制方面的知识差距一直是AKI新疗法开发的一个挫折。我们的研究组之前发现MG53是TRIM家族蛋白的一个新成员，是细胞膜修复机制的重要组成部分。虽然天然的MG53蛋白主要在横纹肌中表达，但它也存在于肾脏，特别是PTE细胞中，浓度很低，但有显著意义。 来自MG53-/-小鼠的PTE细胞比正常细胞更容易受到膜损伤的影响，这一表型也在横纹肌中观察到，这表明MG53有助于肾上皮细胞的修复。与野生型小鼠相比，MG53-/-小鼠出现肾脏疾病，更容易受到I/R诱导的AKI的影响。我们发现，重组人MG53(RhMG53)蛋白可以穿过肾小球，靶向PTE细胞上的损伤部位，从而促进对各种应激的肾脏保护作用。静脉注射rhMG53对大鼠肾脏I/R和顺铂损伤有保护作用。这些数据表明，上调PTE细胞中MG53介导的修复机制可能有助于预防AKI和治疗已建立的AKI。由于天然MG53存在于血液循环中，全身应用rhMG53不太可能诱导免疫反应，可能是治疗AKI的一种安全的生物学方法。该项目的长期目标是验证这一假设，即MG53在生理条件下有助于维持肾功能，靶向MG53介导的PTE细胞损伤修复是预防和治疗AKI的有效手段。我们提出了两个具体的目标：a)阐明MG53介导膜修复在生理和AKI条件下维持肾功能的机制；b)对以rhMG53为基础的预防或治疗AKI的治疗进行概念性研究。这些研究的完成将促进我们对保护肾细胞免受应激损伤的分子机制的了解，并有助于开发预防和治疗AKI的新疗法。

 DESCRIPTION (provided by applicant): Injury to the renal proximal tubular epithelium (PTE) represents the underlying cause for acute kidney injury (AKI) following exposure to various stresses including ischemia-reperfusion (I/R) and nephrotoxins. Kidney cells possess intrinsic mechanisms that can be activated to protect their survival under stress conditions. Facilitating repair of PTE cells will have beneficial effects in the treatment of AKI; however, the knowledge gap in understanding the mechanisms associated with repair of injury to these cells has been a setback in the development of novel therapies for AKI. Our group previously identified MG53, a novel member of the TRIM family protein, as an essential component of the cell membrane repair machinery. Although native MG53 protein is predominantly expressed in striated muscles, it is also present in the kidney particularly in PTE cells at a low, but significant concentration. PTE cells derived from the Mg53-/- mice are more vulnerable to membrane injury than normal cells, a phenotype that is also observed in striated muscles, suggesting that MG53 contributes to repair of renal epithelial cells. Compared with wild type mice, the Mg53-/- mice develop renal disorder and are more susceptible to I/R- induced AKI. We found that the recombinant human MG53 (rhMG53) protein can cross the glomeruli and target to injury sites on PTE cells to facilitate the renal protective effect against various stresses. Intravenous administration of rhMG53 could protect I/R and cisplatin-induced injury to the kidney in rodent models. These data suggest that upregulating the MG53-mediated repair mechanism in PTE cells may be beneficial in preventing AKI and treating established AKI. Since native MG53 is present in circulation, systemic administration of rhMG53 would be unlikely to induce an immune response, and potentially be a safe biologic approach for treatment of AKI. The long-term goal of this project is to test the hypothesis that "MG53 contributes to maintenance of renal function under physiological conditions, and targeting MG53-mediated repair of injury to PTE cells represents an effective means for prevention and treatment of AKI". Two specific aims are proposed: a) to elucidate the mechanism for MG53-mediated membrane repair in maintenance of renal function under physiological and AKI conditions; and b) to conduct proof-of-concept studies on rhMG53- based therapy for prevention or treatment of AKI. Fulfillment of these studies should advance our knowledge on the molecular mechanisms that underlie the protection of renal cells from stress-induced injuries, and help development of novel therapies for prevention and treatment of AKI.