Salt and CHIP: <i>Tet2</i> -CH Aggravates Salt-Sensitive Hypertension in Mice

Hypertension impacts more than a billion people worldwide and is a risk factor for a wide range of age-related diseases, including heart and kidney conditions.Hypertension itself also increases with advancing age for incompletely understood reasons.In this issue of Circulation Research, Polizio et al. present compelling evidence from a series of experiments in mice, demonstrating that infiltration of Tet2-deficient myeloid cells in response to low doses of Angiotensin II (Ang II) promotes renal sodium retention and thus hypertension.1 Their mouse model recapitulates a major subtype of clonal hematopoiesis of indeterminate potential (CHIP), an inflammatory clonal state that affects ≥10% of individuals 65 years and older.CHIP is caused by mutations in hematopoietic stem cells (HSCs; Figure 1A).Experimental work by a number of groups have shown that CHIP-mutated cells disseminate from the bone marrow into peripheral blood and are hyperinflammatory, leading to impaired organ injury responses and chronic damage. 2 CHIP has been associated with a doubling of the risk of several conditions related to hypertension, including coronary artery disease, heart failure, stroke, and chronic kidney disease in observational studies.[3][4][5][6] Prior to this publication, CHIP-affected myeloid cells were known to infiltrate the kidneys and cause damage therein.In 2020, this same research group showed that transplanted bone marrow-derived Tet2-mutated macrophages readily replace renal resident macrophages 7 , and that Tet2-CHIP mice have exacerbated renal fibrosis in response to high dose Ang II infusion (at a rate of 1.5 mg/kg/min).8 Earlier this year, our group showed that Tet2and Jak2-CHIP macrophages infiltrate the kidneys upon ischemic or obstructive kidney injury and display activation of the NLRP3 inflammasome and increased IL-1β production in the kidneys, which ultimately leads to greater kidney fibrosis.9 Polizio et al. now expand upon this knowledge base to show that Tet2-CHIP mice develop hypertension in response low-dose Ang II infusion (200ng/kg/min) while control mice do not (Figure 1B). 1 In a series of experiments, they show that renal infiltration of Tet2-deficient macrophages secreting excess IL-1β activate NKCC2 and NHE3 receptors in the tubules, leading to renal sodium reabsorption, and that the hypertensive phenotype that ensues can be abrogated by inhibiting the NLRP3 inflammasome (Figure 1C). 1 The authors propose that the chemokine CCL5 is required for Tet2-deficient macrophages to localize to the kidney.The upregulation of the

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