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.