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

描述（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）可能通过不依赖血压的作用促进肾损伤。RAS激活免疫系统已被认为是介导这些行为的一种机制。我们发现，长期输注Ang II可引起明显的肾损伤，CD4+ T辅助淋巴细胞浸润肾脏，促炎细胞因子包括干扰素-g （IFN-g）和肿瘤坏死因子-a （TNF-a）的表达增强。广泛作用的免疫抑制剂霉酚酸酯（MMF）消除了这些作用，而不影响血压。因此，我们假设在这种情况下，Ang II激活CD4+ T细胞依赖的细胞免疫反应有助于慢性肾损伤。通常，CD4+ T细胞不直接介导细胞毒性组织损伤。相反，它们通过分化为1型（Th1）或2型（Th2） CD4+ T辅助细胞来调节免疫反应。Th2细胞调节抗体反应，而Th1细胞分泌IFN-g，导致巨噬细胞和细胞毒性CD8+ T细胞活化，介导细胞损伤。活化的巨噬细胞反过来产生TNF-a，进一步刺激Th1细胞。因此，我们认为，Ang II通过I型血管紧张素（AT1）受体促进肾脏中Th1免疫反应的发展，并通过不依赖血压的机制增强IFN-g和TNF-a的产生，直接导致肾脏疾病的进展。为了验证这一点，我们将在小鼠系中检测Ang ii诱导的肾损伤，其遗传修饰影响：关键细胞系中对Th1分化至关重要的转录因子、关键Th1细胞因子和AT1受体反应。除CD4+ T细胞外，IFN-g和TNF-a在多种免疫细胞系甚至肾实质细胞中表达。因此，我们设计了实验来确定这些细胞因子在Ang II依赖性肾损伤中的细胞来源。了解Th1免疫反应如何影响Ang ii诱导的肾损害，将为预防进行性慢性肾脏疾病提供更有效的策略。

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.