Participation of Immune Cells in Klotho Deficiency‐induced Salt‐sensitive Hypertension

Objective Klotho (KL) is an aging‐suppressor gene. The purpose of this study is to investigate if immune cells are involved in KL deficiency‐induced salt‐sensitive hypertension. Methods & Results Haploinsufficiency of KL (+/‐) caused spontaneous and persistent increase in blood pressure (BP). Interestingly, the high salt (HS) intake further increased BP and exacerbated hypertension in KL(+/‐) mice, but not in WT mice, suggesting that KL deficiency elicited salt‐sensitive hypertension. The HS loading remarkably increased expression of MCP‐1 and infiltration of macrophages and T cells in kidneys in KL(+/‐) mice. Blockade of CC chemokine receptor 2 (CCR2) by a CCR2‐specific antagonist (INCB3284) abolished the HS‐induced increase in BP in KL(+/‐) mice, suggesting an important role of monocyte chemotaxis in salt‐sensitive hypertension. INCB3284 abolished infiltration of macrophages and T cells in kidneys in KL(+/‐) mice. The expression of Sgk1, NCC and ATP synthase β in kidneys was enhanced by HS loading in KL(+/‐) mice, which can be eliminated by INCB. Blockade of CCR2 abolished HS‐induced renal structural damage and functional impairment in KL(+/‐) mice. Conclusion KL deficiency caused salt‐sensitive hypertension and renal damage via MCP‐1/CCR2‐mediated inflammation and infiltration of macrophages and T cells.