RNA Sequencing reveals induction of specific renal inflammatory pathways in a rat model of malignant hypertension
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 are well recognized, but the development of malignant nephrosclerosis remains incompletely understood.  Using the rat model of two-kidney, one-clip renovascular hypertension in which some but not all animals develop malignant nephrosclerosis, we performed an unbiased analysis of genes by RNA-sequencing to identify transcriptional changes in the kidney specific for malignant nephrosclerosis. Differential gene expression was assessed in three groups: malignant hypertension (MH), non-malignant hypertension (NMH) and normotensive, sham operated controls (sham). To distinguish MH from NMH, we considered two factors: weight loss and typical renovascular lesions. Mean blood pressure measured intraarterially was elevated to a similar degree in MH (220.0±6.5 mmHg) and NMH (192.0±6.4 mmHg) compared to controls (119.5±1.7 mmHg, p<0.05). 886 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 did previously attract relatively little attention in the setting of hypertensive nephrosclerosis: 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) as well as actual granulocyte infiltration were increased only in MH rats. The data suggest that these pathways may contribute to the most severe forms of hypertensive nephrosclerosis. Overall design: Analysis of gene expression in the kidney in a animal model of renovascular hypertension elucidating the pathogenic background of malignant hypertension using RNA-Seq