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 (+/2) mice and wild-type (WT) mice (9 weeks of age, 16 mice per group). Notably, systolic BP in KL(+/2) 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(+/2) 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(+/2) 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(+/2) mice, and treatment with INCB3284 abolished these effects. Treatment of KL(+/2) mice with INCB3284 also attenuated the increased renal expressions of serum glucocorticoid-regulated kinase 1, thiazide-sensitive NaCl cotransporter, and ATP synthase b 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. 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. Insertional mutation of mouse klotho gene resulted in extensive premature aging phenotypes and shortens lifespan. 1 However, overexpression of mouse klotho gene extended the lifespan by 20%-30% and rescued aging disorders. 2 Therefore, klotho is an antiaging gene.Aging is characterized by age-related deterioration in health. Hypertension is a common agingrelated disorder. The prevalence of hypertension increases with age. 3 On the basis of an epidemiologic study, 3 the prevalence of hypertension is more than doubled in the elderly than the young population. More than two thirds of individuals over age 65 years suffer from hypertension according to the Seventh Report of the Joint National Committee. 4 Salt intake is one of the main environmental factors contributing to the development of hypertension. An increase in salt sensitivity has been noted with advancing age in numerous studies. 5-9 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

Antiaging Gene Klotho Regulates Adrenal CYP11B2 Expression and Aldosterone Synthesis

“…38,39 Our recent study showed that high salt-induced kidney damage in KL(+/2) mice may involve activation of the MCP-1/CCR2 pathway and infiltration of T cells and macrophages. 16 Although we cannot exclude the contribution of hypertension to renal impairment in KL(+/2) mice, consistent results of other studies without the confounding interference of hypertension 7,40,41 suggest that the activated inflammatory process could play an independent and important role in renal damage.…”

“…16 This study further shows that upregulation of aldosterone levels is responsible for the inflammation seen in KL(+/2) mice, because blockade of aldosterone receptors abolishes leukocyte infiltration and cytokine releases in kidneys (Supplemental Figures 4 and 5). Although FGF23 was reported to increase the membrane abundance of NCC, tubular uptake of sodium, and BP in WT mice, high serum levels of FGF23 1,26 failed to increase Na reabsorption and BP in KL(2/2) mice.…”

“…15 We recently reported that KL deficiency causes hypertension and kidney damage. 16 However, the mechanism of KL deficiency-induced hypertension is not fully understood. We hypothesize that haplodeficiency of KL upregulates adrenal CYP11B2 expression and aldosterone synthesis, which contribute to KL deficiencyinduced hypertension and kidney damage.…”

Klotho Ameliorates Kidney Injury and Fibrosis and Normalizes Blood Pressure by Targeting the Renin-Angiotensin System

“…Notably, a recent study has implicated Klotho deficiency in causing salt-sensitive hypertension in mice, 20 supporting the role of Klotho in regulating blood pressure. In view of the fact that RAS activation, not only plays a role in the evolution and progression of CKD, but also is a causative factor for developing hypertension and cardiovascular diseases, 7,45 our studies on the intimate connection between loss of Klotho and RAS activation would have wide implications beyond CKD.…”

Deficiency in the anti‐aging gene Klotho promotes aortic valve fibrosis through AMPK α‐mediated activation of RUNX 2

“…Immunohistochemical (IHC) procedures were performed as described in our previous studies (Crosswhite et al ., 2014; Chen et al ., 2015; Lin & Sun, 2015a,c; Zhou et al ., 2015b). Western blotting was performed as described in our previous studies (Goetz et al ., 2010; Belting et al ., 2012; Chen et al ., 2015; Lin & Sun, 2015b,c; Zhou et al ., 2015a; Lin et al ., 2016). For details, see the Appendix S1 (Supporting information).…”