Inhibition of Cadherin-11 in Chronic Kidney Disease

Cadherin-11 在慢性肾脏病中的抑制作用

基本信息

批准号：
10338151
负责人：
Tessa M Huffstater
金额：
$ 2.39万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-02 至 2022-01-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10338151
关键词：
Acute Renal Failure with Renal Papillary Necrosis Adult Affect Aftercare Angiotensin II Antibodies Aristolochic Acids Biological Markers Biopsy Blocking Antibodies Cadherins Cell Adhesion Molecules Cell Survival Cell-Cell Adhesion Cells Chronic Chronic Kidney Failure Clinical Data Development Disease Disease Progression Disease model Drug Targeting Epithelial Epithelial Cells Event Family Fibroblasts Fibrosis Gene Expression Genetic Human Hydrogen Peroxide In Vitro Inflammatory Injury Injury to Kidney Kidney Kidney Diseases Knockout Mice Link Mediating Mediator of activation protein Metabolic Modeling Molecular Morphology Mus Natural regeneration Nuclear Translocation Pathway interactions Pharmacologic Substance Pharmacology Play Prevalence Production Renal function Research Role Sampling Signal Pathway Signal Transduction Tubular formation United States Urine WNT Signaling Pathway Work base beta catenin cadherin-11 cell type cytokine efficacy testing epithelial injury experimental study immune activation improved improved outcome in vivo inhibitor injured kidney fibrosis mouse model novel preservation prevent prophylactic protective effect protein expression recruit treatment strategy virtual

项目摘要

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.

项目概要慢性肾病 (CKD) 的患病率正在上升，目前影响着美国 15% 的成年人，肾脏损伤后出现慢性肾病 (CKD)，这会引发多种疾病。最终导致肾小管间质纤维化（CKD 的标志）的细胞和分子事件。许多细胞类型参与纤维化的发展，近曲小管上皮细胞是纤维化不可或缺的一部分 CKD 的进展是因为它们的高代谢活性使它们特别容易受伤。上皮细胞分泌促纤维化和炎症细胞因子，介导免疫细胞的募集和因此，近曲小管上皮细胞在 CKD 中发挥着重要作用，因为它们都是最近的一项研究表明，钙粘蛋白 11 (CDH11) 的表达增加。肾纤维化的小鼠模型以及患有 CKD 的人类活组织检查和尿液样本中。 CDH11 已被证明是治疗多种纤维化疾病的有效策略，结合生物标志物数据，促使我们小组研究 CDH11 在肾脏疾病中的作用。我们的初步数据表明 CDH11 抑制。改善多种 CKD 小鼠模型的肾功能、肾小管存活和肾脏形态。模型中，我们发现当通过基因敲除小鼠和预防性药物抑制 CDH11 时，疾病得到缓解我们还发现 CDH11 表达只出现在受伤的细胞中。小鼠和人类的近端肾小管上皮细胞的 CDH11 抑制保护近端肾小管上皮的机制。肾小管上皮细胞尚不清楚，但 CDH11 已被证明与许多信号通路相互作用，包括 Wnt/β-连环蛋白通路。CDH11 的缺失会增加典型的 Wnt/β-连环蛋白信号传导，以及我们的初步数据。表明当肾小管中的 CDH11 受到抑制时，Wnt/β-catenin 信号传导会出现这种增加。上皮细胞与 CKD 模型中肾小管损伤的减少有关，尽管其在慢性损伤中的确切作用我们还不清楚抑制 CDH11 会保护肾功能并减少肾功能。通过对近端肾小管上皮的保护作用，在小鼠 CKD 模型中发现肾小管间质纤维化。使用 CKD 小鼠模型，我们将通过分析野生型之间的差异来评估 CDH11 的效果我们还将使用从野生型和基因敲除小鼠中分离的近端小管细胞。小鼠以确定 CDH11 抑制减轻肾损伤的机制最后，我们将给药。损伤建立后使用功能性阻断抗体来评估 CDH11 抑制是否可以用作 CKD 的治疗策略拟议的研究将是第一个确定 CDH11 在其中的作用的研究。 CKD 并确定 CDH11 抑制是否可以用作 CKD 的治疗策略。