Regulation of colitis associated with acute kidney injury by the Wnt pathway

摘要：克罗恩病患者的肾脏表现或尿路并发症发生率为4%-23% (CD)和溃疡性结肠炎(UC)(各种形式的炎症性肠病，IBD)，通常发生在那些严重的，长期的- 常见病。预防和治疗IBD及其相关的急性肾损伤(AKI)非常重要 临床问题，但治疗性免疫干预的分子靶点仍然难以捉摸。有一个关键的 需要了解结肠炎介导的AKI的免疫学机制，这将指导识别新的 预防或治疗IBD和IBD相关AKI的目标。我们已经确定了一个新的和 规范的Wnt通路作为调节串扰的关键分子通路先前未被发现的作用 在疾病发展过程中，肠道和肾脏之间的联系。我们证明了Wnt配体通过低- 肾抗原提呈细胞(APC)中密度脂蛋白受体相关蛋白5和6(LRP5/6)的表达 用于抑制肾脏和结肠炎介导的AKI的病理性炎症反应。消融这些共同的- 小鼠DC或MPS上的受体导致免疫稳态的丧失，并增强结肠炎介导的AKI。 然而，LRP5/6在肾脏APC中作用的下游机制可以抑制炎症和AKI 是完全未知的。当前提案中的具体目标是(目标1)理解规范如何 WNT途径赋予肾APC调节表型并抑制结肠炎介导的AKI；(AIM2)至 了解肾APC如何通过典型的Wnt信号产生IL-10和维甲酸 抑制肾脏和结肠炎介导的AKI中的氧化应激，并(Aim3)来检查“证据 经典Wnt通路的药理学激活可预防肾炎和结肠炎-- 调解的AKI。建议的研究若能顺利完成，将大大加深我们对 规范的WNT控制肠道炎症反应的机制。重要的是 拟议的研究将提供新的途径来增强Wnt信号的抗炎反应，同时 抑制可能对治疗IBD有显著疗效的病理性炎症反应- 相关的AKI和其他免疫介导的肾脏疾病。

Summary: Renal manifestations or urinary complications occur in 4–23% in patients with Crohn’s disease (CD) and ulcerative colitis (UC) (forms of inflammatory bowel disease, IBD), often in those with severe, long- standing disease. Prevention and treatment of IBD and associated acute kidney injury (AKI) are important clinical problems, but molecular targets for therapeutic immune intervention remain elusive. There is critical need for understanding the immunological mechanisms of colitis-mediated AKI that will guide in identifying new targets for the prevention or treatment of IBD and IBD-associated AKI. We have identified a new and previously unsuspected role for the canonical Wnt pathway as a key molecular pathway in regulating cross‐talk between the gut and kidney during disease progression. We show that Wnt ligands that signal through low- density lipoprotein receptor-related protein 5 and 6 (LRP5/6) in renal antigen presenting cells (APCs) is critical for suppressing pathologic inflammatory response in the kidney and colitis-mediated AKI. Ablation of these co- receptors in DCs or MPs in mice causes loss of immune homeostasis and augments colitis-mediated AKI. However, downstream mechanisms by which LRP5/6 acts in renal APCs act to suppress inflammation and AKI are completely unknown. Specific aims in the current proposal are (Aim 1) to understand how the canonical Wnt pathway imparts regulatory phenotype on renal APCs and suppresses colitis-mediated AKI; (Aim2) to understand how IL-10 and retinoic acid produced by renal APCs in response to canonical Wnt signaling suppresses oxidative stress in the kidney and colitis-mediated AKI, and (Aim3) to examine the “proof of concept” that pharmacological activation of the canonical Wnt pathway prevents renal inflammation and colitis- mediated AKI. The successful completion of the proposed studies will significantly enhance our understanding of the mechanisms by which the canonical Wnt control inflammatory responses in the intestine. Importantly, the proposed studies will provide new avenues to enhance anti-inflammatory response of Wnt signaling while suppressing pathologic inflammatory response that may have significant therapeutic impact in treating IBD- associated AKI and other immune mediated-renal diseases.