Shahbaz Saad

Introduction: Hypertension is a condition that affects over 1 billion people.² It is a leading cause of death worldwide. Hypertension is defined by systolic blood pressure being greater than 140 mm Hg and diastolic blood pressure being > 90 mm Hg^9,10 Men are generally more affected than women, according to the CDC website. Risk factors include a high salt diet, which is what I will focus on in this discussion.  Prevalence of hypertension is 45.4% but could be a lot more since a lot of people are undiagnosed. The pathogenesis of hypertension is multifaceted.^9,10,11 Immunity is a major cause of hypertension, and is the main focus for this project. Methods: DCs become activated by sensing an increase in intracellular Na+ concentration in the intestinal mucosa, where salt is absorbed.² Activated DCs make superoxides via NADPH oxidase.⁴ This environment leads to production of isolevuglandins.¹ When fed a high-salt diet, DCs activate cytokine production.². Isolevuglandins are protein adducts that commonly form in hypertensive environments.⁴ The superoxides that are formed by NADPH Oxidase subsequently forms isolevuglandin adducts.⁵ These isoLG adducts act as neoantigens which cause kidney and vascular dysfunction. ^4,5 Human monocytes can be activated by isoLG protein adducts, which are activated by a high salt-concentration. Causes an autoimmune state Monocytes produce pro-inflammatory cytokines. The scavenging of isoLG adducts may be a viable treatment option for hypertension.^4,5   Results: The cytokines made by DCS activate T-cells which secrete their pro-inflammatory cytokines like Il-17A.²  High-salt environments trigger production of isoLGs.^4,5  Conclusion: Dendritic Cells activate T-Cells, which form pro-inflammatory cytokines which induce hypertension. A high salt-intake can trigger these dendritic cells into doing this. Additionally, a high-salt intake can trigger the formation of isolevuglandin protein adducts, which further mediate hypertension. Targeting the pro-inflammatory cytokines, or the isoLG protein adducts can be treatment options for hypertension.

1. Lu X, Rudemiller NP, Privratsky JR, et al. Classical Dendritic Cells Mediate Hypertension by Promoting Renal Oxidative Stress and Fluid Retention. Hypertension. 2020;75(1):131-138. doi:10.1161/HYPERTENSIONAHA.119.13667
2. Ferguson JF, Aden LA, Barbaro NR, et al. High dietary salt-induced dendritic cell activation underlies microbial dysbiosis-associated hypertension. JCI Insight. 2019;5(13):e126241. Published 2019 Jun 4. doi:10.1172/jci.insight.126241
3. Norlander AE, Saleh MA, Kamat NV, et al. Interleukin-17A Regulates Renal Sodium Transporters and Renal Injury in Angiotensin II-Induced Hypertension. Hypertension. 2016;68(1):167-174. doi:10.1161/HYPERTENSIONAHA.116.07493
4. Barbaro NR, Foss JD, Kryshtal DO, et al. Dendritic Cell Amiloride-Sensitive Channels Mediate Sodium-Induced Inflammation and Hypertension. Cell Rep. 2017;21(4):1009-1020. doi:10.1016/j.celrep.2017.10.002
5. Ruggeri Barbaro N, Van Beusecum J, Xiao L, et al. Sodium activates human monocytes via the NADPH oxidase and isolevuglandin formation. Cardiovasc Res. 2021;117(5):1358-1371. doi:10.1093/cvr/cvaa207
6. Zhang RM, McNerney KP, Riek AE, Bernal-Mizrachi C. Immunity and Hypertension. Acta Physiol (Oxf). 2021;231(1):e13487. doi:10.1111/apha.13487
7.  Lu X, Crowley SD. Actions of immune cells in the hypertensive kidney. Curr Opin Nephrol Hypertens. 2020;29(5):515-522. doi:10.1097/MNH.0000000000000635
8. Van Beusecum JP, Barbaro NR, McDowell Z, et al. High Salt Activates CD11c⁺ Antigen-Presenting Cells via SGK (Serum Glucocorticoid Kinase) 1 to Promote Renal Inflammation and Salt-Sensitive Hypertension. Hypertension. 2019;74(3):555-563. doi:10.1161/HYPERTENSIONAHA.119.12761
9. Rucker AJ, Rudemiller NP, Crowley SD. Salt, Hypertension, and Immunity. Annu Rev Physiol. 2018;80:283-307. doi:10.1146/annurev-physiol-021317-121134
10. Xiao L, Patrick DM, Aden LA, Kirabo A. Mechanisms of isolevuglandin-protein adduct formation in inflammation and hypertension. Prostaglandins Other Lipid Mediat. 2018;139:48-53. doi:10.1016/j.prostaglandins.2018.09.008
11. Lu X, Rudemiller NP, Privratsky JR, et al. Classical Dendritic Cells Mediate Hypertension by Promoting Renal Oxidative Stress and Fluid Retention. Hypertension. 2020;75(1):131-138. doi:10.1161/HYPERTENSIONAHA.119.13667
12. O’Shea PM, Griffin TP, Fitzgibbon M. Hypertension: The role of biochemistry in the diagnosis and management. Clin Chim Acta. 2017;465:131-143. doi:10.1016/j.cca.2016.12.014