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: Xiaoli Zhou, Kai Chen, Han Lei, Zhongjie Sun
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 26 Issue 1 Pg. 121-32 (Jan 2015) ISSN: 1533-3450 [Electronic] United States
• PMID: 24904083 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by the American Society of Nephrology.

Chemical References

• Benzamides
• Ccl2 protein, mouse
• Ccr2 protein, mouse
• Chemokine CCL2
• INCB 3284
• Receptors, CCR2
• Thiazides
• Sodium Chloride
• Glucuronidase
• Klotho Proteins
• Glycine

Topics

• Animals
• Benzamides (chemistry)
• Blood Pressure
• Chemokine CCL2 (metabolism)
• Disease Models, Animal
• Gene Expression Regulation
• Glucuronidase (genetics, physiology)
• Glycine (analogs & derivatives, chemistry)
• Heterozygote
• Hypertension (genetics, pathology)
• Inflammation
• Kidney (drug effects, metabolism)
• Klotho Proteins
• Macrophages (cytology, metabolism)
• Mice
• Mice, Transgenic
• Receptors, CCR2 (metabolism)
• Sodium Chloride (metabolism)
• T-Lymphocytes (cytology)
• Thiazides (chemistry)