Role of Th1 Immune Responses in the Pathogenesis of Hypertensive Kidney Injury

Th1 免疫反应在高血压肾损伤发病机制中的作用

• 批准号: 9253386
• 负责人: Steven D Crowley
• 金额: $ 23.85万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9253386
• 关键词: Adoptive Transfer; Albuminuria; Angiotensin II; Angiotensins; Attenuated; Biological Assay; Blood Pressure; Cell physiology; Cells; Chronic Kidney Failure; Cicatrix; Coculture Techniques; Coupled; Cytokine Suppression; Epithelium; Fibrosis; Generations; Genetic Transcription; Hematopoietic; Hypertension; IL2RA gene; Immune; Immune response; In Vitro; Incubated; Inflammatory; Injury; Kidney; Kidney Diseases; Kidney Transplantation; Knock-out; Lead; Ligands; Literature; Malignant Neoplasms; Mediating; Modeling; Mus; Myeloid Cells; Neoplasm Metastasis; Pathogenesis; Pathway interactions; Patients; Population; Porcupines; Production; Protein Isoforms; Publishing; Receptor, Angiotensin, Type 1; Regulatory T-Lymphocyte; Renin-Angiotensin System; Role; Signal Pathway; Signal Transduction; T cell differentiation; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Testing; Th1 Cells; Time; Tissues; Transplant Recipients; Transplantation; Tubular formation; Wild Type Mouse; base; blood pressure regulation; cell injury; cytokine; in vitro Assay; in vivo; injured; kidney cell; kidney epithelial cell; macrophage; normotensive; novel; prevent; public health relevance; receptor; response; transcription factor; tumor

 DESCRIPTION (provided by applicant): Inappropriate activation of the renin angiotensin system (RAS) makes a critical contribution to the progression of chronic kidney disease (CKD). However, the effects of the RAS effector angiotensin (Ang) II on renal damage are tissue-specific. Stimulating type 1 angiotensin (AT1) receptors in the kidney drives blood pressure elevation and renal injury. By contrast, we have recently established that activating AT1 receptors directly on T lymphocytes suppresses pro-inflammatory Th1 cytokines and protects the kidney. Like angiotensin (Ang II), the transcription factor Twist1 acts in kidney cells to driv renal fibrosis but in immune cells to suppress NF-b-dependent cytokine induction. To explain these analogous actions of Ang II and Twist1, we have discovered that Ang II induces Twist1 expression in macrophages and T lymphocytes. Nevertheless, in our new preliminary studies, Twist1 in T cells promotes blood pressure elevation and albuminuria in the Ang II-dependent hypertension model. This finding is completely unexpected based on the published literature that emphasizes cytokine suppression by Twist1 in T cells. Resolving this paradox, NF- B activation also drives transcription of TGF- 9, a key effector cytokine of CD4+CD25+ T regulatory cells whose adoptive transfer can blunt the hypertensive response. We find that Twist1 in T cells limits the emergence of these CD4+CD25+ T cells following NF-B stimulation. We therefore hypothesize that Twist1 in T cells promotes hypertension and renal injury during RAS activation by suppressing T regulatory cell functions. To test this hypothesis, we will subject mice lacking Twist1 solely in T cells to models of RAS- dependent hypertension and kidney damage. Whereas TGF- in T lymphocytes mediates T regulatory cell functions, TGF- in macrophages drives kidney fibrosis during RAS activation. Consistent with this notion, in our preliminary studies, Twist1-deficiency in macrophages permits exaggerated TGF- and TNF- expression, leading to augmented RAS-dependent kidney damage and fibrosis. However, we now find that these same cytokines can induce several Wnt ligand isoforms in kidney epithelial cells and that blocking Porcupine (PORC)-dependent secretion of these Wnts dramatically attenuates the extent of kidney damage and fibrosis. Thus, we posit that Twist1 in macrophages protects the kidney from injury and fibrosis by limiting cytokine-dependent Wnt generation in kidney epithelial cells. We will test this possibility using unpublished models of macrophage-specific Twist1 deficiency and kidney-specific PORC deficiency in conjunction with our kidney cross-transplantation strategy. Collectively, our studies will define for the first time the contribution of Twist1 in hematopoietic cell populations to blood pressure regulation and will discriminate novel mechanisms through which Twist1 modulates kidney damage and fibrosis. Given the importance of Twist1 not only to fibrosis but also to tumor metastasis, establishing these cell-specific actions of Twist1 in vivo will be critical to allow targeting of this pathway i patients with hypertension, tissue fibrosis, and cancer.

 描述（由申请方提供）：肾素血管紧张素系统（RAS）的不适当激活对慢性肾脏疾病（CKD）的进展起关键作用。然而，RAS效应血管紧张素（Ang）II对肾损伤的影响是组织特异性的。刺激肾脏中的1型血管紧张素（AT 1）受体会导致血压升高和肾损伤。相比之下，我们最近已经确定，直接激活T淋巴细胞上的AT 1受体抑制促炎性Th 1细胞因子，并保护肾脏。与血管紧张素（Ang II）一样，转录因子Twist 1在肾细胞中起作用以驱动肾纤维化，但在免疫细胞中起作用以抑制NF-κ B依赖性细胞因子诱导。为了解释Ang II和Twist 1的这些类似作用，我们发现Ang II诱导巨噬细胞和T淋巴细胞中的Twist 1表达。然而，在我们新的初步研究中，T细胞中的Twist 1促进了Ang II依赖性高血压模型中的血压升高和蛋白尿。基于强调T细胞中Twist 1对细胞因子抑制的已发表文献，这一发现完全出乎意料。为了解决这个矛盾，NF-κ B B活化也驱动TGF-β 9的转录，TGF-β 9是CD 4 + CD 25+调节性T细胞的关键效应细胞因子，其过继转移可以减弱高血压反应.我们发现T细胞中的Twist 1限制了NF-κ B B刺激后这些CD 4 + CD 25 + T细胞的出现。因此，我们假设T细胞中的Twist 1通过抑制T调节细胞功能，在RAS激活过程中促进高血压和肾损伤。为了验证这一假设，我们将对T细胞中缺乏Twist 1的小鼠进行RAS依赖性高血压和肾损伤模型。而T淋巴细胞中的TGF-β介导T调节细胞功能，巨噬细胞中的TGF-β在RAS激活期间驱动肾纤维化。与这一观点一致，在我们的初步研究中，巨噬细胞中的Twist 1缺陷允许过度的TGF-β和TNF-β表达，导致RAS依赖性肾损伤和纤维化增加。然而，我们现在发现，这些相同的细胞因子可以在肾上皮细胞中诱导几种Wnt配体亚型，并且阻断豪猪（PORC）依赖的这些Wnt分泌可以显著减轻肾损伤和纤维化的程度。因此，我们证实巨噬细胞中的Twist 1通过限制肾上皮细胞中的精氨酸依赖性Wnt产生来保护肾脏免受损伤和纤维化。我们将使用未发表的巨噬细胞特异性Twist 1缺陷和肾脏特异性PORC缺陷模型结合我们的肾脏交叉移植策略来测试这种可能性。总的来说，我们的研究将首次定义Twist 1在造血细胞群体中对血压调节的贡献，并将区分Twist 1调节肾损伤和纤维化的新机制。考虑到Twist 1不仅对纤维化而且对肿瘤转移的重要性，在体内建立Twist 1的这些细胞特异性作用对于允许靶向高血压、组织纤维化和癌症患者中的该途径至关重要。