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.
Highlights
In 1997, a new aging suppressor gene was identified and named after the purported Greek Moira Klotho,[1] who spins the thread of life and controls the ultimate destiny of humans
Because the klotho level decreases with age, whereas renal function declines with age,[11] we investigated if one-half klotho deficiency causes renal damage, with a focus on the underlying mechanism
The results revealed, for the first time, that one-half klotho deficiency increased salt sensitivity and caused salt-sensitive hypertension
Summary
In 1997, a new aging suppressor gene was identified and named after the purported Greek Moira Klotho,[1] who spins the thread of life and controls the ultimate destiny of humans. An increase in salt sensitivity has been noted with advancing age in numerous studies.[5,6,7,8,9] Salt sensitivity is more common in the old than the young population. The relationship of age and salt sensitivity seems to be stronger in hypertensive than. Normotensive individuals.[8] It was reported that salt sensitivity was present in approximately 50% of hypertensive individuals,[40] years old but increased to over 80% in those .60 years old.[10] Xiao et al.[11] reported that the klotho level in serum declines with age in humans after 40 years of age. The klotho level decreases and the salt sensitivity increases with age, it is not clear if klotho deficiency enhances salt sensitivity. The objective of this study is to investigate if one-half klotho deficiency affects salt sensitivity and investigate the underlying mechanism in klotho mutant heterozygous (+/2 [KL(+/2)]) mice
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