Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany.
J Mol Med (Berl). 2021 Dec;99(12):1727-1740. doi: 10.1007/s00109-021-02133-8. Epub 2021 Sep 15.
In malignant hypertension, far more severe kidney injury occurs than in the "benign" form of the disease. The role of high blood pressure and the renin-angiotensin-aldosterone system is well recognized, but the pathogenesis of the renal injury of malignant hypertension (MH) remains incompletely understood. Using the rat model of two-kidney, one-clip renovascular hypertension in which some but not all animals develop MH, we performed a transcriptomic analysis of gene expression by RNA sequencing to identify transcriptional changes in the kidney cortex specific for MH. Differential gene expression was assessed in three groups: MH, non-malignant hypertension (NMH), and normotensive, sham-operated controls. To distinguish MH from NMH, we considered two factors: weight loss and typical renovascular lesions. Mean blood pressure measured intraarterially was elevated in MH (220 ± 6.5 mmHg) as well as in NMH (192 ± 6.4 mmHg), compared to controls (119 ± 1.7 mmHg, p < 0.05). Eight hundred eighty-six genes were exclusively regulated in MH only. Principal component analysis revealed a separated clustering of the three groups. The data pointed to an upregulation of many inflammatory mechanisms in MH including pathways which previously attracted relatively little attention in the setting of hypertensive kidney injury: Transcripts from all three complement activation pathways were upregulated in MH compared to NMH but not in NMH compared with controls; immunohistochemistry confirmed complement deposition in MH exclusively. The expression of chemokines attracting neutrophil granulocytes (CXCL6) and infiltration of myeloperoxidase-positive cells were increased only in MH rats. The data suggest that these pathways, especially complement deposition, may contribute to kidney injury under MH. KEY MESSAGES: The most severe hypertension-induced kidney injury occurs in malignant hypertension. In a rat model of malignant hypertension, we assessed transcriptional responses in the kidney exposed to high blood pressure. A broad stimulation of inflammatory mechanisms was observed, but a few specific pathways were activated only in the malignant form of the disease, notably activation of the complement cascades. Complement inhibitors may alleviate the thrombotic microangiopathy of malignant hypertension even in the absence of primary complement abnormalities.
在恶性高血压中，肾脏损伤比“良性”形式更为严重。高血压和肾素-血管紧张素-醛固酮系统的作用已得到充分认识，但恶性高血压（MH）肾损伤的发病机制仍不完全清楚。我们使用两肾一夹型肾血管性高血压大鼠模型，其中一些但不是所有动物都会发展为 MH，通过 RNA 测序进行了基因表达的转录组分析，以鉴定 MH 特有的肾皮质转录变化。在三个组中评估了差异基因表达：MH、非恶性高血压（NMH）和正常血压、假手术对照。为了将 MH 与 NMH 区分开来，我们考虑了两个因素：体重减轻和典型的肾血管病变。通过动脉内测量，MH 组的平均血压升高（220±6.5mmHg），NMH 组（192±6.4mmHg）也升高，而对照组（119±1.7mmHg，p<0.05）。886 个基因仅在 MH 中受到调节。主成分分析显示三组聚类分离。数据表明 MH 中许多炎症机制上调，包括在高血压肾损伤背景下以前受到较少关注的途径：与 NMH 相比，MH 中所有三种补体激活途径的转录本均上调，但与对照组相比则没有；免疫组织化学证实 MH 中仅存在补体沉积。趋化因子吸引中性粒细胞（CXCL6）的表达和髓过氧化物酶阳性细胞的浸润仅在 MH 大鼠中增加。这些数据表明，这些途径，特别是补体沉积，可能在 MH 下导致肾脏损伤。关键信息：最严重的高血压引起的肾脏损伤发生在恶性高血压中。在恶性高血压大鼠模型中，我们评估了暴露于高血压的肾脏中的转录反应。观察到广泛的炎症机制刺激，但只有少数特定途径仅在疾病的恶性形式中被激活，特别是补体级联的激活。即使在没有原发性补体异常的情况下，补体抑制剂也可能缓解恶性高血压的血栓性微血管病。
