Inhibition of Cadherin-11 in Chronic Kidney Disease

项目摘要 慢性肾脏疾病（CKD）的患病率正在增加，目前影响美国15%的成年人， 而且治疗方法也非常有限CKD是在肾脏损伤后出现的， 最终导致肾小管间质纤维化（CKD的标志）的细胞和分子事件。虽然 许多细胞类型参与纤维化的发展，近端小管上皮细胞是纤维化的组成部分。 慢性肾脏病的进展，因为他们的高代谢活动使他们特别容易受伤。受伤 上皮细胞分泌促纤维化和炎症细胞因子，其介导免疫细胞的募集， 成纤维细胞的活化。因此，近曲小管上皮细胞在CKD中起重要作用，因为它们都是 慢性损伤的目标和介质。最近的一项研究表明，在乳腺癌患者中，钙粘蛋白-11（CDH 11）的表达增加， 小鼠肾纤维化模型以及患有CKD的人的活组织检查和尿液样品中。抑制 CDH 11已被证明是几种纤维化疾病的有效策略，结合生物标志物数据， 促使我们的小组研究肾脏疾病中的CDH 11。我们的初步数据显示， 在多种CKD小鼠模型中改善肾功能、肾小管存活和肾脏形态。在每个 在模型中，我们发现当通过基因敲除小鼠和预防性药物抑制CDH 11时， 施用功能性阻断抗体。我们还发现，CDH 11的表达仅限于损伤的 近端小管上皮细胞。CDH 11抑制保护近端 肾小管上皮细胞是未知的，但CDH 11已被证明与许多信号通路，包括 Wnt/β-catenin途径。CDH 11的缺失增加了经典的Wnt/β-catenin信号传导，我们的初步数据显示， 这表明当CDH 11在受损的肾脏中受到抑制时这种增加。肾小管上皮细胞中Wnt/β-catenin信号转导 上皮细胞与CKD模型中肾小管损伤的减少有关，尽管在慢性损伤中的确切作用 并没有得到很好的理解。我们假设抑制CDH 11将保护肾功能并降低肾功能。 通过对近端小管上皮的保护作用，在小鼠CKD模型中抑制肾小管间质纤维化。 使用CKD的小鼠模型，我们将通过分析野生型和非野生型之间的差异来评估CDH 11的作用。 和基因敲除小鼠。我们还将使用分离的近端小管细胞从野生型和基因敲除 小鼠以确定CDH 11抑制减轻肾损伤的机制。最后，我们将管理 建立损伤后的功能性阻断抗体，以评估是否可以通过 作为CKD的治疗策略。这项拟议的研究将是第一个确定CDH 11在 CKD，并确定CDH 11抑制是否可用作CKD的治疗策略。

PROJECT SUMMARY Chronic kidney disease (CKD) is increasing in prevalence, currently affecting 15% of adults in the United States, and treatment options are extremely limited. CKD arises after an injury to the kidney, which sets off several cellular and molecular events that eventually result in tubulointerstitial fibrosis, the hallmark of CKD. Although many cell types are involved in the development of fibrosis, proximal tubule epithelial cells are integral to the progression of CKD because their high metabolic activity makes them particularly susceptible to injury. Injured epithelial cells secrete pro-fibrotic and -inflammatory cytokines that mediate the recruitment of immune cells and activation of fibroblasts. Therefore, proximal tubule epithelial cells play a significant role in CKD, as they are both a target and mediator of chronic injury. A recent study has shown increased cadherin-11 (CDH11) expression in mouse models of kidney fibrosis as well as in biopsies and urine samples of humans with CKD. Inhibition of CDH11 has proven an effective strategy in several fibrotic diseases, which, combined with the biomarker data, prompted our group to investigate CDH11 in kidney disease. Our preliminary data shows that CDH11 inhibition improves renal function, tubular survival, and kidney morphology in multiple murine models of CKD. In each model, we found disease mitigation when CDH11 was inhibited via both genetic knockout mice and prophylactic administration of a functional blocking antibody. We also found that CDH11 expression was exclusive to injured proximal tubule epithelia in both mice and humans. The mechanism by which CDH11 inhibition protects proximal tubule epithelia is unknown, but CDH11 has been shown to interact with many signaling pathways, including the Wnt/β-catenin pathway. Loss of CDH11 increases canonical Wnt/β-catenin signaling, and our preliminary data suggests such an increase when CDH11 is inhibited in the injured kidney. Wnt/β-catenin signaling in tubular epithelial cells has been linked to reduced tubular injury in CKD models, although the exact role in chronic injury is not well understood. We hypothesize that inhibition of CDH11 will preserve renal function and reduce tubulointerstitial fibrosis in models of CKD in mice through protective effects on the proximal tubule epithelium. Using mouse models of CKD, we will evaluate the effects of CDH11 by analyzing differences between wild type and genetic knockout mice. We will also use isolated proximal tubule cells from wild type and genetic knockout mice to determine the mechanisms by which CDH11 inhibition mitigates renal injury. Finally, we will administer a functional blocking antibody following establishment of injury to evaluate whether CDH11 inhibition could be used as a treatment strategy for CKD. The proposed research will be the first to determine the role of CDH11 in CKD and determine whether CDH11 inhibition could be used as a treatment strategy for CKD.