Macrophage Polarization and Renal Migration in the Etiology of Hypertension
Introduction. Heart disease is the greatest cause of death in the United States.1 Hypertension represents the most important modifiable risk factor implicated in heart disease,2 representing a major risk factor in coronary and peripheral atherosclerosis, cardiac hypertrophy3, heart failure, ischemic stroke, intracerebral hemorrhage and chronic end-stage renal disease.3 The causes of hypertension are multifactorial.3 By definition, “Essential Hypertension” has no specific identifiable cause. 90% of hypertension is classified as essential, a combination of genetics and environment.3 Methods. The Spontaneous Hypertensive Rat (SHR) has upregulated CD161+ proinflammatory cells compared to the WKY wildtype. These CD68+/CD161+ macrophages represent classically polarized M1 macrophages in SHRs.4,7 Hypertension symptomology observed in SHRs is phenotypically inbred in these mice as a model organism for studying essential hypertension.7 Nicotine infused SHRs were euthanized and renal digests, uranalysis, serum tests and immunohistochemistry performed to measure differential inflammation. Results. Nicotine stimulates macrophage polarization, through adrenergic stimulation or artificial stimulation.4 Polarization and activation of macrophages primes the inflammatory state. Nicotinic activation of CD161a+/CD68+ macrophages induces renal infiltration.4 Increased production of CCR2/MCP1 also recruits renal macrophages to infiltrate the kidney.5 Renal macrophage infiltration results in inflammation.4 Inflammation was mediated by a CCR2 inhibitor.5 IL-17 also mediates inflammation in SHRs.8 Inflammation, vascularization and other downstream effects of NLRP3 Inflammasome activation cause end organ damage.6 End organ renal damage is associated with renal hypertension.7 Conclusions. Hypertension still represents the most modifiable risk factor for heart disease, and heart disease represents the largest cause of death next to death itself. Renal hypertension represents both a cause and effect of systemic hypertension, and for these reasons it merits study. Polarization of macrophages and renal infiltration and inflammation start the mechanism of pathogenesis presented here. There are many causes of inflammation and macrophage polarization, as numerous as the causes of cellular damage and stress. One study examined nicotinic stimulation of macrophage polarization in SHRs, a model organism used to study inherited hypertension. Activation and infiltration of M1 macrophages (CD68+ marking monocyte cellular lineage, and CD161a+ marking a special population of activated macrophages found upregulated in SHRs) travel toward the higher CCL2 concentration gradient by chemotaxis, infiltrating the kidney causing inflammation and subsequent renal damage. This migration could also occur between CD161a+ macrophages and LTT-1. Part of renal damage occurs through the stimulation of CaSR and resulting action of the inflammasome and release of inflammatory mediators.
- Centers for Disease Control and Prevention (CDC), National Center for Health Statistics (NCHS). Underlying Cause of Death 1999-2013 on CDC WONDER Online Database, released 2015. Data are from the Multiple Cause of Death Files, 1999-2013, as compiled from data provided by the 57 vital statistics jurisdictions through the Vital Statistics Cooperative Program. https://www.cdc.gov/heartdisease/facts.htm. Accessed February 28, 2019.
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- Harwani SC, Ratcliff J, Sutterwala FS, et al. Nicotine Mediates CD161a+ Renal Macrophage Infiltration and Premature Hypertension in the Spontaneously Hypertensive Rat. Circ Res. 2016 Oct 28; 119(10): 1101–1115. Published online 2016 Sep 22. doi: 10.1161/CIRCRESAHA.116.309402
- Kashyap S, Warner GM, Hartono SP, et al. Blockade of CCR2 reduces macrophage influx and development of chronic renal damage in murine renovascular hypertension. Am J Physiol Renal Physiol. 2016; 310: F372–F384. First published December 9, 2015; doi:10.1152/ajprenal.00131.2015.
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- Harwani SC. Macrophages under pressure: the role of macrophage polarization in hypertension. Translational Research 191. 2018;45-63.
- Singh MV, Cicha MZ, Kumar S, et al. ABNORMAL CD161+ IMMUNE CELLS AND RORγt MEDIATED ENHANCED IL-17F EXPRESSION IN GENETIC HYPERTENSION. J Allergy Clin Immunol. 2017 September ; 140(3): 809–821.e3. doi:10.1016/j.jaci.2016.11.039.