title: Klotho gene deficiency causes salt-sensitive hypertension via monocyte chemotactic protein-1/CC chemokine receptor 2-mediated inflammation.
abstract: Klotho (KL) is a newly discovered aging suppressor gene. In mice, the KL gene extends the lifespan when overexpressed and shortens the lifespan when disrupted. This study investigated if KL deficiency affects BP and salt sensitivity using KL mutant heterozygous (+/-) mice and wild-type (WT) mice (9 weeks of age, 16 mice per group). Notably, systolic BP in KL(+/-) mice began to increase at the age of 15 weeks, reached a peak level at the age of 17 weeks, and remained elevated thereafter, whereas systolic BP remained consistent in WT mice. High salt (HS) intake further increased BP in KL(+/-) mice but did not affect BP in WT mice. Blockade of CC chemokine receptor 2 (CCR2), involved in monocyte chemotaxis, by a specific CCR2 antagonist (INCB3284) abolished the HS-induced increase in BP in KL(+/-) mice. Furthermore, HS loading substantially increased the expression of monocyte chemotactic protein-1 and the infiltration of macrophages and T cells in kidneys in KL(+/-) mice, and treatment with INCB3284 abolished these effects. Treatment of KL(+/-) mice with INCB3284 also attenuated the increased renal expressions of serum glucocorticoid-regulated kinase 1, thiazide-sensitive NaCl cotransporter, and ATP synthase β along with the renal structural damage and functional impairment induced by HS loading. In conclusion, KL deficiency caused salt-sensitive hypertension and renal damage by CCR2-mediated inflammation.
authors.affiliation: Department of Cardiology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China; and Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Kai
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Cardiology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China; and.
authors.forename: Han
authors.initials: H
authors.lastname: Lei
authors.affiliation: Department of Cardiology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China; and Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma Zhongjie-sun@ouhsc.edu.
authors.forename: Zhongjie
authors.initials: Z
authors.lastname: Sun
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry; D001794:Blood Pressure; D018932:Chemokine CCL2 / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005966:Glucuronidase / Q000235:genetics* / Q000502:physiology; D005998:Glycine / Q000031:analogs & derivatives / Q000737:chemistry; D006579:Heterozygote; D006973:Hypertension / Q000235:genetics* / Q000473:pathology; D007249:Inflammation; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D000090265:Klotho Proteins; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D054390:Receptors, CCR2 / Q000378:metabolism; D012965:Sodium Chloride / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology; D049971:Thiazides / Q000737:chemistry
chemical_list: D001549:Benzamides; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; C000595924:INCB 3284; D054390:Receptors, CCR2; D049971:Thiazides; D012965:Sodium Chloride; D005966:Glucuronidase; D000090265:Klotho Proteins; D005998:Glycine
keywords: cardiovascular; hypertension; monocyte chemotactic protein-1