Difficult-to-control blood pressure in non-diabetic hypertensive subjects is associated with upregulated gene expression of inflammatory pathways

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Introduction: Hypertension (HTN) causes cardiovascular disease. Despite this, many patients do not achieve blood pressure (BP) control. We hypothesized that non-diabetic hypertensive subjects with difficult-to-control BP will activate predictive signaling pathways.

Methods: We collected demographics and 24-h and first-morning urine collections from 61 subjects enrolled in the Systolic Blood Pressure Intervention Trial (SPRINT). A validated instrument was administered to asses sugar sweetened beverage intake and converted to grams fructose per day. The BP-Difficult (BPD) group had SBP >140 mmHg or >120 mmHg for intensive group subjects, or BP at “goal” for the trial group and more than the median number of agents in each group in study as a whole. The “BP Easy” group (BPE) comprised the remainder of subjects. Mean BP from two visits before SPRINT termination established the study BP. Gene expression from transcriptomic sequencing of cellular RNAs of first-morning urine were assessed for differential expression (DE) genes (>1.5-fold change; P<0.01) by the Wilcoxon Rank-Sum test and pathway analysis.

Results: Recoverable RNA from 51 subjects was present in 33 BPD and 18 BPE subjects. In the BPD group, 338 genes were upregulated and 3 downregulated; pathway analysis identified interferon, phosphoinositide 3-kinase, B cell receptor, and inducible nitric oxide synthase signaling as key upregulated pathways (P<0.05). Most upregulated genes were components of pro-inflammatory pathways: interferon (IFNAR1), interleukin-2 and -4 (IL2RG, IL4R), tumor necrosis factor receptor (TNFRSF1B), and infiltrating B lymphocytes (PIK3AP1). BPD subjects with low 24-h urine sodium (<200 mmol) and fructose intake (<40 g/day) had 59 DE genes: 57 upregulated and 2 downregulated. Significant pathways included STAT3 and Cdc42 signaling pathways (P<0.05), and IL2RG, MAPK14, TGFB1, and IFNAR1 were components of these pathways.

Conclusions: Urinary cells from a difficult-to-control BP SPRINT cohort demonstrated molecular signatures associated with specific pro-inflammatory pathways and immune mediators.






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