Targeting cell membrane repair for treatment of acute kidney injury

 描述（由申请方提供）：肾近端小管上皮（PTE）损伤是暴露于各种应激（包括缺血-再灌注（I/R）和肾毒素）后急性肾损伤（阿基）的根本原因。肾细胞具有内在的机制，可以被激活，以保护其在应激条件下的生存。促进PTE细胞的修复将在阿基的治疗中具有有益的效果;然而，在理解与这些细胞损伤修复相关的机制方面的知识差距已经成为阿基新疗法开发的一个挫折。我们的小组先前确定了MG 53，TRIM家族蛋白的新成员，作为细胞膜修复机制的重要组成部分。虽然天然MG 53蛋白主要在横纹肌中表达，但它也以低但显著的浓度存在于肾脏中，特别是在PTE细胞中。 来自Mg 53-/-小鼠的PTE细胞比正常细胞更容易受到膜损伤，这也是在横纹肌中观察到的表型，表明MG 53有助于肾上皮细胞的修复。与野生型小鼠相比，Mg 53-/-小鼠发生肾脏疾病并且更容易受到I/R诱导的阿基。我们发现，重组人MG 53（rhMG 53）蛋白可以穿过肾小球并靶向PTE细胞上的损伤部位，以促进肾脏对各种应激的保护作用。静脉注射rhMG 53对大鼠I/R和顺铂所致的肾脏损伤具有保护作用。这些数据表明，上调PTE细胞中MG 53介导的修复机制可能有益于预防阿基和治疗已建立的阿基。由于天然MG 53存在于循环中，因此rhMG 53的全身给药不太可能诱导免疫应答，并且可能是治疗阿基的安全生物学方法。该项目的长期目标是验证“MG 53有助于在生理条件下维持肾功能，靶向MG 53介导的PTE细胞损伤修复是预防和治疗阿基的有效手段”的假设。提出了两个具体目的：a）阐明MG 53介导的膜修复在生理和阿基条件下维持肾功能的机制;和B）对基于rhMG 53的治疗预防或治疗阿基进行概念验证研究。这些研究的完成将促进我们对保护肾细胞免受应激诱导损伤的分子机制的了解，并有助于开发预防和治疗阿基的新疗法。

 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.