The interleukin-1 receptor regulates crosstalk between myeloid and renal tubular cells in hypertension

世界卫生组织估计，高血压影响世界上40%的成年人口。尽管 高血压的灾难性心血管并发症，如中风、充血性心力衰竭， 慢性肾脏疾病（CKD），血压仍然控制不佳，在一半以上的患者携带 诊断7。SPRINT试验证明了严格控制血压的好处，强调了需要 开发新的药物，以进一步降低血压和限制高血压的靶器官损害。的 最近认识到先天性免疫反应有助于高血压及其并发症， 促进开发新的高血压免疫调节干预措施。然而，扰乱 炎症介质的促高血压作用而不诱导有害的免疫抑制将需要 阐明了先天免疫应答驱动血液的离散细胞特异性机制 血压升高和随后的终末器官损伤。循环单核细胞和组织巨噬细胞是关键 白细胞介素-1（IL-1）是由促炎性细胞因子产生的典型细胞因子， 巨噬细胞我们在小鼠高血压模型中发现，基因缺失或药物阻断 IL-1受体（IL-1 R1）的表达增强一氧化氮（NO）的尿排泄，减少肾钠 保留，抑制NKCC 2转运蛋白，并限制血压升高。因此，我们假设， 肾上皮细胞上的IL-1受体活化抑制其NO的产生，从而促进 钠在肾单位的重吸收为了验证这一假设，我们将检查肾钠转运，NO 在肾单位特异性IL-1 R 1缺乏（IL-1 R）的小鼠模型中， KKO）。用血管紧张素受体阻断剂（ARB）和利尿剂治疗这些动物将确定添加剂 废除肾上皮细胞中IL-1 R1信号的临床益处并阐明下游机制 肾单位中的白细胞介素1受体通过此途径升高血压。不受控制的高血压和其他原因 CKD最终导致不可逆的肾纤维化。NO也可以减轻肾纤维化，我们新的初步数据表明， 表明髓细胞特异性IL-1 R缺失减轻了驱动肾纤维化的缺血性损伤。我们 因此，证实肾内巨噬细胞中的IL-1 R1活化减弱了它们的NO生成， 加剧了肾纤维化我们将直接检测巨噬细胞中IL-1 R1对肾纤维化的作用 通过从小鼠的骨髓细胞中遗传切除IL-1 R1（IL-1 RKKO）并使这些动物经受损伤， 引发肾纤维化通过这种逐步的方法，我们将发现互补的，细胞特异性的作用， IL-1 R1依赖性血压调节和肾损伤可以支持新的 高血压的免疫调节疗法。

The World Health Organization estimates that hypertension impacts 40% of the world’s adult population. Despite the catastrophic cardiovascular complications of hypertension such as stroke, congestive heart failure, and chronic kidney disease (CKD), blood pressure remains poorly controlled in more than half of patients carrying the diagnosis 7. The SPRINT trial demonstrated the benefits of tight blood pressure control, highlighting the need to develop novel agents to further reduce blood pressure and limit target organ damage in hypertension. The recent recognition that innate immune responses contribute to hypertension and its complications should facilitate the development of novel immunomodulatory interventions for hypertension. However, disrupting the pro-hypertensive actions of inflammatory mediators without inducing harmful immunosuppression will require elucidation of the discrete cell-specific mechanisms through which innate immune responses drive blood pressure elevation and consequent end organ injury. Circulating monocytes and tissue macrophages are key effectors of innate immunity, and interleukin-1 (IL-1) is the prototypical cytokine produced by pro-inflammatory macrophages. We have found in a murine hypertension model that genetic deletion or pharmacologic blockade of the receptor for IL-1 (IL-1R1) enhances urinary excretion of nitric oxide (NO), attenuates renal sodium retention, inhibits the NKCC2 transporter, and limits blood pressure elevation. We therefore hypothesize that IL-1 receptor activation on kidney epithelial cells suppresses their generation of NO and thereby promotes sodium reabsorption in the nephron. To test this hypothesis, we will examine renal sodium transport, NO generation, and susceptibility to hypertension in a murine model of nephron-specific IL-1R1 deficiency (IL-1R KKO). Treating these animals with angiotension receptor blockade (ARB) and diuretics will identify additive clinical benefits of abrogating IL-1R1 signals in kidney epithelial cells and elucidate downstream mechanisms through which the IL-1R in the nephron raises blood pressure. Uncontrolled hypertension and other causes of CKD culminate in irreversible kidney fibrosis. NO can also attenuate renal fibrosis, and our new preliminary data suggest that myeloid cell-specific deletion of IL-1R mitigates ischemic damage that drives renal fibrogenesis. We therefore posit that IL-1R1 activation in intra-renal macrophages attenuates their generation of NO and exacerbates kidney fibrosis. We will directly test the contribution of IL-1R1 in macrophages to kidney fibrogenesis by genetically excising IL-1R1 from myeloid cells in mice (IL-1R KKO) and subjecting these animals to insults that trigger renal fibrosis. With this stepwise approach, we will discover complementary, cell-specific actions of IL-1R1-dependent blood pressure regulation and kidney damage that can underpin the development of novel immunomodulatory therapies for hypertension.