Long-term excessive dietary phosphate increases arterial blood pressure, activates the renin-angiotensin-aldosterone system, and stimulates sympathetic tone in mice

Increased dietary phosphate intake has been associated with severity of coronary artery disease, increased carotid intima–media thickness, left ventricular hypertrophy (LVH), and increased cardiovascular mortality and morbidity in individuals with nor-mal renal function as well as in patients suffering from chronic kidney disease. How-ever, the underlying mechanisms are still unclear. To elucidate further the cardiovas-cular sequelae of long-term elevated phosphate intake we maintained male C57BL/6 mice on a calcium, phosphate, and lactose‐enriched diet (CPD, 2% Ca, 1.25% P, 20% lactose) after weaning for 14 months and compared them with age-matched male mice fed a normal mouse diet (ND, 1.0% Ca, 0.7% P). Notably, the CPD has a balanced cal-cium/phosphate ratio, allowing to investigate the effects of elevated dietary phosphate intake largely independent of changes in parathyroid hormone (PTH). In agreement with the rationale of this experiment, mice maintained on CPD for 14 months were characterized by unchanged serum PTH but showed elevated concentrations of circu-lating intact fibroblast growth factor-23 (FGF23) compared with mice on ND. Cardio-vascular phenotyping did not provide evidence for LVH, as evidenced by unchanged LV chamber size, normal cardiomyocyte area, lack of fibrosis, and unchanged molecu-lar markers of hypertrophy (Bnp) between the two groups. However, intra-arterial catheterization revealed increases in systolic pressure, mean arterial pressure, and pulse pressure in mice fed the CPD. Interestingly, chronically elevated dietary phos-phate intake stimulated the renin-angiotensin-aldosterone system (RAAS) as evi-denced by increased urinary aldosterone in animals fed the CPD, relative to ND con-trols. Furthermore, the catecholamines epinephrine, norepinephrine, and dopamine as well as the catecholamine metabolites metanephrine. normetanephrine and methoxy-tyramine as measured by mass spectrometry were elevated in the urine of mice on CPD, relative to mice on ND. These changes were partially reversed by switching 14-month-old mice on CPD back to ND for 2 weeks. In conclusion, our data suggest that excess dietary phosphate induces a rise in blood pressure independent of second-ary hyperparathyroidism, and that this effect may be mediated through activation of the RAAS and stimulation of the sympathetic tone.