The link between immunity and hypertension in the kidney and heart

Abstract

Hypertension is the primary cause of cardiovascular disease, which is a leading killer worldwide. Despite the prevalence of this non-communicable disease, still between 90% and 95% of cases are of unknown or multivariate cause ("essential hypertension"). Current therapeutic options focus primarily on lowering blood pressure through decreasing peripheral resistance or reducing fluid volume, but fewer than half of hypertensive patients can reach blood pressure control. Hence, identifying unknown mechanisms causing essential hypertension and designing new treatment accordingly are critically needed for improving public health. In recent years, the immune system has been increasingly implicated in contributing to a plethora of cardiovascular diseases. Many studies have demonstrated the critical role of the immune system in the pathogenesis of hypertension, particularly through pro-inflammatory mechanisms within the kidney and heart, which, eventually, drive a myriad of renal and cardiovascular diseases. However, the precise mechanisms and potential therapeutic targets remain largely unknown. Therefore, identifying which immune players are contributing to local inflammation and characterizing pro-inflammatory molecules and mechanisms involved will provide promising new therapeutic targets that could lower blood pressure and prevent progression from hypertension into renal or cardiac dysfunction.

Keywords: heart; hypertension; immunity; inflammation; kidney.

Figure 1

The contributions of the innate and adaptive immunity to kidney damage during hypertension with various activating stimuli and subsequent cytokine production. Sources below: Macrophages: IL-1β (Veiras et al., 2022, Circulation Research, secondary hypertension), TNFα (Singh et al., 2013 American Journal of Physiology: Renal Physiology, essential hypertension). Dendritic Cells: Mineralcorticoids (Araos et al., 2019 Journal of Hypertension, secondary hypertension), ROS (Lu et al., 2020 Hypertension, essential hypertension), and Isoketals (Kirabo et al., 2014, Journal of Hypertension, essential hypertension). T Cells: IL-17 (Kamat et al., 2015, Hypertension, essential hypertension), IFNγ (Benson et al., 2022 Circulation Research and Kamat et al., 2015, Hypertension, essential hypertension). B Cells: (Chan et al., 2015 Hypertension.)

Figure 2

Macrophages and their mechanistic role in fibrosis. M2 macrophages can interact with αVβ6, thereby releasing a TGF-β inhibitor protein, and allowing them to interact with fibroblasts in the heart. TGF-β leads to myofibroblast differentiation from fibroblasts via the SMAD2/3 pathway. It is these myofibroblasts that are thought to account for much of the fibrotic remodeling in many diseases, including diastolic dysfunction and heart failure.

Figure 3

The outcome of ROS production on cardiomyocyte function. Soluble Guanylate Cyclase (sGC) drives Myosin II dephosphorylation and smooth muscle relaxation via production of the secondary messenger cGMP. sGC is activated by intercellular NO produced by endothelial nitric oxide synthase (eNOS). Reactive oxygen species inhibit eNOS activity, thereby affecting cardiomyocyte function further downstream. sGC enhancers target sGC at an allosteric site to increase its sensitivity to NO, thereby rescuing function despite lower NO availability.

Figure 4

Immune cells known to express receptors antagonized by current antihypertensives and known change in signaling or function as a result of receptor antagonism.