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)的不适当激活在慢性肾脏疾病(CKD)的进展中起着至关重要的作用。然而，RAS效应因子血管紧张素(Ang)II对肾脏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(AT1)受体会导致血压升高和肾脏损伤。相比之下，我们最近证实，直接激活T淋巴细胞上的AT1受体可以抑制致炎的Th1细胞因子，保护肾脏。与血管紧张素II一样，转录因子Twist1在肾细胞中作用于肾纤维化，但在免疫细胞中作用于抑制核因子-b依赖的细胞因子的诱导。为了解释Ang II和Twist1的这些类似作用，我们发现Ang II诱导巨噬细胞和T淋巴细胞表达Twist1。然而，在我们新的初步研究中，T细胞中的Twist1促进了Ang II依赖型高血压模型中的血压升高和蛋白尿。这一发现完全出乎人们的意料，因为已发表的文献强调了T细胞中Twist1抑制细胞因子的作用。解决这一矛盾的是，NF-B的激活也推动了转化生长因子9的转录，转化生长因子9是CD4CD25T调节细胞的关键效应细胞因子，其过继转移可以钝化高血压反应。我们发现T细胞中的Twist1限制了在NF-B刺激后这些CD4CD25T细胞的出现。因此，我们假设T细胞中的Twist1通过抑制T调节细胞功能来促进RAS激活过程中的高血压和肾脏损伤。为了验证这一假设，我们将在T细胞中单独缺失Twist1的小鼠进行RAS依赖性高血压和肾脏损伤的模型。T淋巴细胞中的转化生长因子-介导T细胞的调节功能，而巨噬细胞中的转化生长因子-在RAS激活过程中促进肾脏纤维化。与这一概念一致，在我们的初步研究中，巨噬细胞中Twist1缺乏允许过度表达转化生长因子-和肿瘤坏死因子-，导致RAS依赖的肾脏损伤和纤维化加剧。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，并且阻断这些WNT依赖于豪猪(Porc)的分泌可以显著减轻肾脏损伤和纤维化的程度。因此，我们假设巨噬细胞中的Twist1通过限制肾上皮细胞中细胞因子依赖的Wnt的产生来保护肾脏免受损伤和纤维化。我们将结合我们的肾脏交叉移植策略，使用未发表的巨噬细胞特异性Twist1缺乏症和肾脏特异性Pporc缺乏症模型来测试这种可能性。总而言之，我们的研究将首次确定Twist1在造血细胞群体中对血压调节的贡献，并将区分Twist1调节肾脏损伤和纤维化的新机制。鉴于Twist1不仅对纤维化而且对肿瘤转移的重要性，在体内建立Twist1的这些细胞特异性作用对于靶向高血压、组织纤维化和癌症患者的这一途径将是至关重要的。

 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.