title: Nicotine Mediates CD161a+ Renal Macrophage Infiltration and Premature Hypertension in the Spontaneously Hypertensive Rat.
abstract: BACKGROUND
  Renal inflammation contributes to the pathophysiology of hypertension. CD161a+immune cells are dominant in the (SHR) spontaneously hypertensive rat and expand in response to nicotinic cholinergic activation.
  
  
  OBJECTIVE
  We aimed to phenotype CD161a+immune cells in prehypertensive SHR after cholinergic activation with nicotine and determine if these cells are involved in renal inflammation and the development of hypertension.
  
  
  RESULTS
  Studies used young SHR and WKY (Wistar-Kyoto) rats. Splenocytes and bone marrow cells were exposed to nicotine ex vivo, and nicotine was infused in vivo. Blood pressures, kidney, serum, and urine were obtained. Flow cytometry, Luminex/ELISA, immunohistochemistry, confocal microscopy, and Western blot were used. Nicotinic cholinergic activation induced proliferation of CD161a+/CD68+macrophages in SHR-derived splenocytes, their renal infiltration, and premature hypertension in SHR. These changes were associated with increased renal expression of MCP-1 (monocyte chemoattractant protein-1) and VLA-4 (very-late antigen-4). LLT1 (lectin-like transcript 1), the ligand for CD161a, was overexpressed in SHR kidney, whereas vascular cellular and intracellular adhesion molecules were similar to those in WKY. Inflammatory cytokines were elevated in SHR kidney and urine after nicotine infusion. Nicotine-mediated renal macrophage infiltration/inflammation was enhanced in denervated kidneys, not explained by angiotensin II levels or expression of angiotensin type-1/2 receptors. Moreover, expression of the anti-inflammatory α7-nAChR (α7-nicotinic acetylcholine receptor) was similar in young SHR and WKY rats.
  
  
  CONCLUSIONS
  A novel, inherited nicotinic cholinergic inflammatory effect exists in young SHR, measured by expansion of CD161a+/CD68+macrophages. This leads to renal inflammation and premature hypertension, which may be partially explained by increased renal expression of LLT-1, MCP-1, and VLA-4.
authors.affiliation: From the Department of Internal Medicine (S.C.H., J.R., F.S.S., Z.K.B., M.W.C., F.M.A.), Departments of Molecular Physiology and Biophysics (M.W.C., F.M.A.), and Veterans Affairs Medical Center (F.S.S., Z.K.B., M.W.C.), Iowa City; and Department of Pathology (D.K.M.), Inflammation Program, Department of Internal Medicine (F.S.S.), Center for Immunology and Immune Mediated Diseases (S.C.H., F.S.S., F.M.A.), and Abboud Cardiovascular Research Center (S.C.H., J.R., M.W.C., F.M.A.), University of Iowa Carver College of Medicine, Iowa City. sailesh-harwani@uiowa.edu.
authors.forename: Sailesh C
authors.initials: SC
authors.lastname: Harwani
authors.affiliation: From the Department of Internal Medicine (S.C.H., J.R., F.S.S., Z.K.B., M.W.C., F.M.A.), Departments of Molecular Physiology and Biophysics (M.W.C., F.M.A.), and Veterans Affairs Medical Center (F.S.S., Z.K.B., M.W.C.), Iowa City; and Department of Pathology (D.K.M.), Inflammation Program, Department of Internal Medicine (F.S.S.), Center for Immunology and Immune Mediated Diseases (S.C.H., F.S.S., F.M.A.), and Abboud Cardiovascular Research Center (S.C.H., J.R., M.W.C., F.M.A.), University of Iowa Carver College of Medicine, Iowa City.
authors.forename: Jason
authors.initials: J
authors.lastname: Ratcliff
authors.affiliation: From the Department of Internal Medicine (S.C.H., J.R., F.S.S., Z.K.B., M.W.C., F.M.A.), Departments of Molecular Physiology and Biophysics (M.W.C., F.M.A.), and Veterans Affairs Medical Center (F.S.S., Z.K.B., M.W.C.), Iowa City; and Department of Pathology (D.K.M.), Inflammation Program, Department of Internal Medicine (F.S.S.), Center for Immunology and Immune Mediated Diseases (S.C.H., F.S.S., F.M.A.), and Abboud Cardiovascular Research Center (S.C.H., J.R., M.W.C., F.M.A.), University of Iowa Carver College of Medicine, Iowa City.
authors.forename: Fayyaz S
authors.initials: FS
authors.lastname: Sutterwala
authors.affiliation: From the Department of Internal Medicine (S.C.H., J.R., F.S.S., Z.K.B., M.W.C., F.M.A.), Departments of Molecular Physiology and Biophysics (M.W.C., F.M.A.), and Veterans Affairs Medical Center (F.S.S., Z.K.B., M.W.C.), Iowa City; and Department of Pathology (D.K.M.), Inflammation Program, Department of Internal Medicine (F.S.S.), Center for Immunology and Immune Mediated Diseases (S.C.H., F.S.S., F.M.A.), and Abboud Cardiovascular Research Center (S.C.H., J.R., M.W.C., F.M.A.), University of Iowa Carver College of Medicine, Iowa City.
authors.forename: Zuhair K
authors.initials: ZK
authors.lastname: Ballas
authors.affiliation: From the Department of Internal Medicine (S.C.H., J.R., F.S.S., Z.K.B., M.W.C., F.M.A.), Departments of Molecular Physiology and Biophysics (M.W.C., F.M.A.), and Veterans Affairs Medical Center (F.S.S., Z.K.B., M.W.C.), Iowa City; and Department of Pathology (D.K.M.), Inflammation Program, Department of Internal Medicine (F.S.S.), Center for Immunology and Immune Mediated Diseases (S.C.H., F.S.S., F.M.A.), and Abboud Cardiovascular Research Center (S.C.H., J.R., M.W.C., F.M.A.), University of Iowa Carver College of Medicine, Iowa City.
authors.forename: David K
authors.initials: DK
authors.lastname: Meyerholz
authors.affiliation: From the Department of Internal Medicine (S.C.H., J.R., F.S.S., Z.K.B., M.W.C., F.M.A.), Departments of Molecular Physiology and Biophysics (M.W.C., F.M.A.), and Veterans Affairs Medical Center (F.S.S., Z.K.B., M.W.C.), Iowa City; and Department of Pathology (D.K.M.), Inflammation Program, Department of Internal Medicine (F.S.S.), Center for Immunology and Immune Mediated Diseases (S.C.H., F.S.S., F.M.A.), and Abboud Cardiovascular Research Center (S.C.H., J.R., M.W.C., F.M.A.), University of Iowa Carver College of Medicine, Iowa City.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Chapleau
authors.affiliation: From the Department of Internal Medicine (S.C.H., J.R., F.S.S., Z.K.B., M.W.C., F.M.A.), Departments of Molecular Physiology and Biophysics (M.W.C., F.M.A.), and Veterans Affairs Medical Center (F.S.S., Z.K.B., M.W.C.), Iowa City; and Department of Pathology (D.K.M.), Inflammation Program, Department of Internal Medicine (F.S.S.), Center for Immunology and Immune Mediated Diseases (S.C.H., F.S.S., F.M.A.), and Abboud Cardiovascular Research Center (S.C.H., J.R., M.W.C., F.M.A.), University of Iowa Carver College of Medicine, Iowa City.
authors.forename: Francois M
authors.initials: FM
authors.lastname: Abboud
mesh_terms: D017668:Age of Onset; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003714:Denervation; D005786:Gene Expression Regulation / Q000187:drug effects; D006973:Hypertension / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006977:Hypertension, Renal / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016130:Immunophenotyping; D039041:Integrin alpha4beta1 / Q000096:biosynthesis / Q000235:genetics; D007668:Kidney / Q000294:innervation / Q000473:pathology*; D037102:Lectins / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000145:classification / Q000187:drug effects* / Q000473:pathology; D008297:Male; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000032:analysis; D009393:Nephritis / Q000139:chemically induced / Q000503:physiopathology; D009538:Nicotine / Q000494:pharmacology* / Q000633:toxicity; D009638:Norepinephrine / Q000378:metabolism; D058246:Prehypertension / Q000209:etiology / Q000235:genetics / Q000473:pathology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis / Q000235:genetics; D044139:Receptor, Angiotensin, Type 2 / Q000096:biosynthesis / Q000235:genetics; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000096:biosynthesis / Q000235:genetics; D000097382:CD68 Molecule
chemical_list: D000804:Angiotensin II; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018932:Chemokine CCL2; D016207:Cytokines; D039041:Integrin alpha4beta1; D037102:Lectins; D055651:NK Cell Lectin-Like Receptor Subfamily B; D009538:Nicotine; D009638:Norepinephrine; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D064569:alpha7 Nicotinic Acetylcholine Receptor; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C491768:Ccl2 protein, mouse; C000618297:LLT1 protein, mouse
keywords: CD161; CD68; SHR; cholinergic; hypertension; inflammation; innate immunity; integrin; lectin; macrophage; nicotine; renal