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

世界卫生组织估计，高血压影响着全球40%的成年人口。尽管 高血压的灾难性心血管并发症，如中风、充血性心力衰竭和 慢性肾脏疾病(CKD)，超过一半的患者血压控制不佳 诊断7.Sprint试验证明了严格控制血压的好处，强调了 开发新的药物，进一步降低血压，限制高血压的靶器官损害。这个 最近认识到先天免疫反应会导致高血压及其并发症 促进针对高血压的新型免疫调节干预措施的开发。然而，扰乱了 在不引起有害免疫抑制的情况下炎性介质的促高血压作用将需要 阐明先天免疫反应驱动血液的离散细胞特异性机制 压力升高和随之而来的终末器官损伤。循环中的单核细胞和组织巨噬细胞是关键 先天免疫的效应者，而白介素1(IL-1)是由促炎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 白介素1受体(IL-1R1)增加尿中一氧化氮(NO)的排泄，降低肾脏钠 抑制NKCC2转运体，并限制血压升高。因此，我们假设 肾上皮细胞上IL-1受体的激活抑制其NO的产生，从而促进 钠在肾单位重吸收。为了验证这一假设，我们将检查肾脏的钠转运，不 肾单位特异性IL-1R缺陷(IL-1R)小鼠模型的产生及其对高血压的易感性 KKO)。用血管紧张素受体阻滞剂(ARB)和利尿剂治疗这些动物将确定添加剂 阻断肾上皮细胞IL-1R1信号的临床意义及其下游机制 肾单位中的IL-1R通过这一途径升高血压。失控高血压和其他导致高血压的原因 慢性肾脏病最终导致不可逆转的肾脏纤维化。NO还可以减轻肾脏纤维化，我们的新初步数据 提示髓系细胞特异性IL-1R的缺失可以减轻导致肾纤维化的缺血性损伤。我们 因此假设肾内巨噬细胞中IL-1R1的激活可减少其NO的产生和 会加剧肾脏纤维化。我们将直接检测巨噬细胞中IL-1R1在肾脏纤维化中的作用 通过从小鼠骨髓细胞中基因切除IL-1R1(IL-1R kko)并使这些动物受到侮辱 会引发肾脏纤维化。通过这种循序渐进的方法，我们将发现补充性的、细胞特有的 IL-1R1依赖的血压调节和肾脏损害可支持新型药物的开发 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.