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

描述（由申请人提供）：肾素-血管紧张素系统（RAS）在慢性肾损伤的发病机制中起关键作用。RAS抑制剂的临床试验表明血管紧张素II（Ang II）可能通过血压非依赖性作用促进肾损伤。RAS激活免疫系统被认为是介导这些作用的一种机制。我们已经发现，慢性输注血管紧张素II导致显著的肾损伤，CD 4 + T辅助淋巴细胞浸润到肾脏中，以及促炎细胞因子包括干扰素-g（IFN-g）和肿瘤坏死因子-α（TNF-α）的表达增强。广泛作用的免疫抑制剂mycyphenolate mofetil（MMF）的管理废除了这些影响，而不影响血压。因此，我们假设血管紧张素II激活CD 4 + T细胞依赖性细胞免疫应答导致慢性肾损伤。通常，CD 4 + T细胞不直接介导细胞毒性组织损伤。相反，它们通过分化成1型（Th 1）或2型（Th 2）CD 4 + T辅助细胞来调节免疫应答。Th 2细胞调节抗体应答，而Th 1细胞分泌IFN-g，导致巨噬细胞和细胞毒性CD 8 + T细胞活化，介导细胞损伤。活化的巨噬细胞进而产生TNF-α，其进一步刺激Th 1细胞。因此，我们认为，血管紧张素II通过I型血管紧张素（AT 1）受体的作用，促进了Th 1免疫反应在肾脏中的发展，增强生产的IFN-γ和TNF-α直接导致进行性肾脏疾病通过血压非依赖性机制。为了验证这一点，我们将研究血管紧张素II诱导的肾损伤的小鼠品系与遗传修饰的影响：转录因子的关键Th 1分化，关键Th 1细胞因子，和AT 1受体的反应，在关键细胞系。除了CD 4 + T细胞之外，IFN-g和TNF-α还由几种免疫细胞谱系甚至由肾实质细胞表达。因此，我们设计了实验来鉴定这些细胞因子在血管紧张素II依赖性肾损伤中的细胞来源。了解Th 1免疫应答如何影响血管紧张素II诱导的肾损伤，应导致更有效的策略，以预防进行性慢性肾脏疾病。 公共卫生相关性：高血压是慢性肾脏疾病的常见原因。该提案探讨了T淋巴细胞亚群（Th 1细胞）的活化如何导致血管紧张素II依赖性高血压的肾损伤。了解Th 1免疫应答如何影响血管紧张素II诱导的肾损伤，将有助于制定更有效的预防慢性肾脏疾病进展的策略。

DESCRIPTION (provided by applicant): The renin-angiotensin system (RAS) plays a key role in the pathogenesis of chronic kidney injury. Clinical trials with RAS inhibitors suggest angiotensin II (Ang II) may promote renal injury through blood pressure- independent effects. Activation of the immune system by the RAS has been suggested as one mechanism mediating these actions. We have found that chronic infusion of Ang II causes significant kidney injury, infiltration of CD4+ T helper lymphocytes into the kidney, and enhanced expression of pro-inflammatory cytokines including interferon-g (IFN-g) and tumor necrosis factor-a (TNF-a). Administration of the broadly acting immunosuppressive agent mycyophenolate mofetil (MMF) abrogated these effects without affecting blood pressure. Accordingly, we hypothesize that activation of a CD4+ T cell-dependent cellular immune response by Ang II contributes to chronic kidney damage in this setting. Typically, CD4+ T cells do not directly mediate cytotoxic tissue injury. Rather, they regulate immune responses by differentiating into type 1 (Th1) or type 2 (Th2) CD4+ T helper cells. Whereas Th2 cells regulate antibody responses, Th1 cells secrete IFN-g leading to activation of macrophages and cytotoxic CD8+ T cells to mediate cellular damage. Activated macrophages in turn produce TNF-a, which further stimulates Th1 cells. We therefore suggest that Ang II acting through type I angiotensin (AT1) receptors promotes the development of a Th1 immune response in the kidney, with enhanced production of IFN-g and TNF-a leading directly to progressive kidney disease through blood pressure-independent mechanisms. To test this, we will examine Ang II-induced kidney injury in mouse lines with genetic modifications impacting: transcription factors critical for Th1 differentiation, key Th1 cytokines, and AT1 receptor responses in key cell lineages. In addition to CD4+ T cells, IFN-g and TNF-a are expressed by several immune cell lineages and even by renal parenchymal cells. Therefore, we have designed experiments to identify the cellular sources of these cytokines in Ang II- dependent kidney injury. Understanding how Th1 immune responses influence Ang II-induced renal damage should lead to more effective strategies for preventing progressive chronic kidney disease. PUBLIC HEALTH RELEVANCE: Hypertension is a common cause of chronic kidney disease. This proposal explores how activation of a subset of T lymphocytes (Th1 cells) leads to kidney injury in angiotensin II-dependent hypertension. Understanding how Th1 immune responses influence angiotensin II-induced renal damage should lead to more effective strategies for preventing progressive chronic kidney disease.