Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. High phosphate diet increases arterial blood pressure via a parathyroid hormone mediated increase of renin Milica Bozic a , Sara Panizo a , Maria A. Sevilla b , Marta Riera c , Maria J. Soler c , Julio Pascual c , Ignacio Lopez d , Montserrat Freixenet a , Elvira Fernandez a,e , and Jose M. Valdivielso a Background: There is growing evidence suggesting that phosphate intake is associated with blood pressure levels. However, data from epidemiological studies show inconsistent results. Method and results: The present study was designed to evaluate the effect of high circulating phosphorus on arterial blood pressure of healthy rats and to elucidate the potential mechanism that stands behind this effect. Animals fed a high phosphate diet for 4 weeks showed an increase in blood pressure, which returned to normal values after the addition of a phosphate binder (lanthanum carbonate) to the diet. The expression of renin in the kidney was higher, alongside an increase in plasma renin activity, angiotensin II (Ang II) levels and left ventricular hypertrophy. The addition of the phosphate binder blunted the increase in renin and Ang II levels. The levels of parathyroid hormone (PTH) were also higher in animals fed a high phosphate diet, and decreased when the phosphate binder was present in the diet. However, blood P levels remained elevated. A second group of rats underwent parathyroidectomy and received a continuous infusion of physiological levels of PTH through an implanted mini-osmotic pump. Animals fed a high phosphate diet with continuous infusion of PTH did not show an increase in blood pressure, although blood P levels were elevated. Finally, unlike with verapamil, the addition of losartan to the drinking water reverted the increase in blood pressure in rats fed a high phosphate diet. Conclusion: The results of this study suggest that a high phosphate diet increases arterial blood pressure through an increase in renin mediated by PTH. Keywords: angiotensin II, hypertension, phosphate binder, phosphorus, parathyroid hormone Abbreviations: Ach, acetylcholine; Ca, calcium; CAD, coronary artery disease; CKD, chronic kidney disease; FGF23, fibroblast growth factor 23; LVH, left ventricular hypertrophy; PRA, Plasma renin activity; PTH, parathyroid hormone; PTX, parathyroidectomy; RAAS, renin– angiotensin–aldosterone system; SNP, sodium nitroprusside INTRODUCTION P hosphorus (P) is an essential nutrient in many phys- iological processes in the body and is a critical component of virtually all enzymes and cellular messengers [1]. The homeostasis of P is finely regulated by three important hormones, parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23) and vitamin D. PTH is secreted by the parathyroid glands and has a vital role in regulating mineral metabolism and bone homeostasis by binding to the PTH1R receptor [2]. An increase in blood P promotes PTH secretion [3,4], resulting in decreased P reabsorption from the renal proximal tubule. In addition, PTH increases transcription and secretion of FGF23 in bone [5], which further increases renal P excretion. 1,25 dihy- droxyvitamin D3 (calcitriol), the active form of vitamin D, has the opposite effect, stimulating the reabsorption of P and calcium (Ca) in the renal tubule and in the intestine, leading to the elevation of serum P levels [6]. High circulating P levels have been associated with cardiovascular disease events and mortality in chronic kid- ney disease (CKD) patients [7], as well as in individuals with normal renal function [8]. The exact mechanism is unknown, but it could involve direct effects of P in the endothelium [9], in the development of vascular calcification [10], or indirect effects mediated by P-regulated hormones. Indeed, although the presence of receptors for PTH in the cardio- vascular system is controversial, clinical studies have dem- onstrated an independent role of PTH on cardiovascular mortality [11]. Furthermore, administration of exogenous PTH has been shown to increase renin levels in experimen- tal studies [12,13]. Another P-regulated hormone, calcitriol, also shows direct effects on the vascular system. Indeed, calcitriol has been shown to increase proliferation [14] and calcification [15] of vascular smooth muscle cells. Another potential effect of calcitriol in the cardiovascular system is related to its role in the regulation of renin expression [16]. Therefore, there is a potential role of P levels on blood pressure. The mediators of this effect could include direct Journal of Hypertension 2014, 32:1822–1832 a Nephrology Research Laboratory, Institute for Biomedical Research, IRB Lleida, b Department of Physiology and Pharmacology, University of Salamanca, Salamanca, c Department of Nephrology, Hospital del Mar-IMIM, Barcelona, d Department of Medicine and Animal Surgery, University of Cordoba, Cordoba and e Department of Nephrology and UDETMA, University Hospital Arnau de Vilanova, Lleida, Spain Correspondence to Jose ´ Manuel Valdivielso, PhD, Nephrology Research Laboratory, Institute for Biomedical Research, IRBLLEIDA, Rovira Roure 80, Edificio Biomedicina 1. Laboratory B1-10, 25198 Lleida, Spain. Tel: +973003650; fax: +973702213; e-mail: valdivielso@medicina.udl.cat Received 14 January 2014 Revised 6 May 2014 Accepted 6 May 2014 J Hypertens 32:1822–1832 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000261 1822 www.jhypertension.com Volume 32  Number 9  September 2014 Original Article