CoChat
Sign Up
Cited by 14Parathyroid Disorders and TreatmentsRenin-Angiotensin System StudiesBlood Pressure and Hypertension Studies

Long-Term Excessive Dietary Phosphate Intake Increases Arterial Blood Pressure, Activates the Renin–Angiotensin–Aldosterone System, and Stimulates Sympathetic Tone in Mice

Open access
Latic, Nejla, Peitzsch, Mirko, Zupcic, Ana, Pietzsch, Jens, Erben, Reinhold G.·2022·Biomedicines
DOI 10.3390/biomedicines10102510PMC PMC9599363
Open this paper in CoChat — free accountOpen PDF

Abstract

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 normal renal function as well as in patients suffering from chronic kidney disease. However, the underlying mechanisms are still unclear. To further elucidate the cardiovascular 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 them 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 calcium/phosphate ratio, allowing the effects of elevated dietary phosphate intake largely independent of changes in parathyroid hormone (PTH) to be investigated. 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 circulating intact fibroblast growth factor-23 (FGF23) compared with mice on ND. Cardiovascular phenotyping did not provide evidence for LVH, as evidenced by unchanged LV chamber size, normal cardiomyocyte area, lack of fibrosis, and unchanged molecular 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 phosphate intake stimulated the renin–angiotensin–aldosterone system (RAAS) as evidenced by increased urinary aldosterone in animals fed the CPD, relative to the ND controls. Furthermore, the catecholamines epinephrine, norepinephrine, and dopamine as well as the catecholamine metabolites metanephrine. normetanephrine and methoxytyramine as measured by mass spectrometry were elevated in the urine of mice on CPD, relative to mice on the 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 secondary hyperparathyroidism, and that this effect may be mediated through activation of the RAAS and stimulation of the sympathetic tone.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3390/biomedicines10102510

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Data from animal studies and healthy subjects indicate that longer treatment with high Pi can lead to cardiac remodeling in animals and higher blood pressure in humans.

    “Data from animal studies and healthy subjects indicate that longer treatment with high Pi can lead to cardiac remodeling in animals and higher blood pressure in humans [19, 35, 42].”

    From Controlled dietary phosphate loading in healthy young men elevates plasma phosphate and FGF23 levels (2025) · cites this paper as [35]

    The Discussion (page unavailable) reports a small blood-pressure increase in healthy people given a high-phosphate diet, and Results §3.2 reports that earlier mouse studies found left ventricular hypertrophy. But this paper’s own 14-month mouse experiment found no hypertrophy or other evidence of cardiac remodeling, and the cited passage does not establish that the human blood-pressure increase followed longer treatment. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 48

  1. [1]Peacock M. Phosphate Metabolism in Health and Disease Calcif. Tissue Res. 2020 108 3 15 10.1007/s00223-020-00686-3 32266417 · DOI
  2. [2]Foley R.N. Parfrey P.S. Sarnak M.J. Clinical epidemiology of cardiovascular disease in chronic renal disease Am. J. Kidney Dis. 1998 32 S112 S119 10.1053/ajkd.1998.v32.pm9820470 9820470 · DOI
  3. [3]Go A.S. Chertow G.M. Fan D. McCulloch C.E. Hsu C.Y. Chronic Kidney Disease and the Risks of Death, Cardiovascular Events, and Hospitalization N. Engl. J. Med. 2004 351 1296 1305 10.1056/NEJMoa041031 15385656 · DOI · Paper page
  4. [4]Chang A.R. Grams M.E. Serum Phosphorus and Mortality in the Third National Health and Nutrition Examination Survey (NHANES III): Effect Modification by Fasting Am. J. Kidney Dis. 2014 64 567 573 10.1053/j.ajkd.2014.04.028 24935232 PMC4177334 · DOI
  5. [5]Wang Q. Cui Y. Yogendranath P. Wang N. Blood pressure and heart rate variability are linked with hyperphosphatemia in chronic kidney disease patients Chrono-Int. 2018 35 1329 1334 10.1080/07420528.2018.1486850 29947550 · DOI
  6. [6]Jankowski J. Floege J. Fliser D. Böhm M. Marx N. Cardiovascular Disease in Chronic Kidney Disease Circulation 2021 143 1157 1172 10.1161/CIRCULATIONAHA.120.050686 33720773 PMC7969169 · DOI
  7. [7]Shang D. Xie Q. Ge X. Yan H. Tian J. Kuang D. Hao C.H. Zhu T. Hyperphosphatemia as an independent risk factor for coronary artery calcification progression in peritoneal dialysis patients BMC Nephrol. 2015 16 107 10.1186/s12882-015-0103-8 26187601 PMC4506628 · DOI
  8. [8]Dhingra R. Sullivan L. Fox C.S. Wang T.J. D’Agostino R.B. Gaziano J.M. Vasan R.S. Relations of Serum Phosphorus and Calcium Levels to the Incidence of Cardiovascular Disease in the Community Arch. Intern. Med. 2007 167 879 885 10.1001/archinte.167.9.879 17502528 · DOI · Paper page
  9. [9]Foley R.N. Collins A.J. Herzog C.A. Ishani A. Kalra P.A. Serum Phosphate and Left Ventricular Hypertrophy in Young Adults: The Coronary Artery Risk Development in Young Adults Study Kidney Blood Press. Res. 2009 32 37 44 10.1159/000203348 19229116 · DOI
  10. [10]Mohammad J. Scanni R. Bestmann L. Hulter H.N. Krapf R. A Controlled Increase in Dietary Phosphate Elevates BP in Healthy Human Subjects J. Am. Soc. Nephrol. 2018 29 2089 2098 10.1681/ASN.2017121254 30021759 PMC6065082 · DOI · Paper page
  11. [11]Mills K.T. Stefanescu A. He J. The global epidemiology of hypertension Nat. Rev. Nephrol. 2020 16 223 237 10.1038/s41581-019-0244-2 32024986 PMC7998524 · DOI
  12. [12]Patel R.K. Jeemon P. Stevens K.K. Mccallum L. Hastie C.E. Schneider A. Jardine A.G. Mark P.B. Padmanabhan S. Association between serum phosphate and calcium, long-term blood pressure, and mortality in treated hypertensive adults J. Hypertens. 2015 33 2046 2053 10.1097/HJH.0000000000000659 26431193 · DOI
  13. [13]E Olivo R. Hale S.L. Diamantidis C.J. A Bhavsar N. Tyson C.C. Tucker K.L. Carithers T. Kestenbaum B. Muntner P. Tanner R.M. Dietary Phosphorus and Ambulatory Blood Pressure in African Americans: The Jackson Heart Study Am. J. Hypertens. 2018 32 94 103 10.1093/ajh/hpy126 30107444 PMC6284751 · DOI
  14. [14]Moe S.M. Chen N.X. Pathophysiology of Vascular Calcification in Chronic Kidney Disease Circ. Res. 2004 95 560 567 10.1161/01.RES.0000141775.67189.98 15375022 · DOI
  15. [15]Jono S. McKee M.D. Murry C.E. Shioi A. Nishizawa Y. Mori K. Morii H. Giachelli C.M. Phosphate Regulation of Vascular Smooth Muscle Cell Calcification Circ. Res. 2000 87 E10 E17 10.1161/01.RES.87.7.e10 11009570 · DOI
  16. [16]Giachelli C.M. Vascular Calcification: In Vitro Evidence for the Role of Inorganic Phosphate J. Am. Soc. Nephrol. 2003 14 S300 S304 10.1097/01.ASN.0000081663.52165.66 12939385 · DOI
  17. [17]Van T.V. Watari E. Taketani Y. Kitamura T. Shiota A. Tanaka T. Tanimura A. Harada N. Nakaya Y. Yamamoto H. Dietary phosphate restriction ameliorates endothelial dysfunction in adenine-induced kidney disease rats J. Clin. Biochem. Nutr. 2012 51 27 32 10.3164/jcbn.11-96 22798709 PMC3391860 · DOI
  18. [18]Sancho J.J. Rouco J. Riera-Vidal R. Sitges-Serra A. Long-term effects of parathyroidectomy for primary hyperparathyroidism on arterial hypertension World J. Surg. 1992 16 732 735 10.1007/BF02067371 1413842 · DOI
  19. [19]Bozic M. Panizo S. Sevilla M.A. Riera M. Soler M.J. Pascual J. Lopez I. Freixenet M. Fernandez E. Valdivielso J.M. High phosphate diet increases arterial blood pressure via a parathyroid hormone mediated increase of renin J. Hypertens. 2014 32 1822 1832 10.1097/HJH.0000000000000261 24979301 · DOI
  20. [20]Jowsey J. Reiss E. Canterbury J.M. Long-Term Effects of High Phosphate Intake on Parathyroid Hormone Levels and Bone Metabolism Acta Orthop. Scand. 1974 45 801 808 10.3109/17453677408989691 4463682 · DOI
  21. [21]Demeter J.G. A De Jong S. Oslapas R. Ernst K. Hessel P. Jarosz H. Smith M. Nayyar R. Lawrence A.M. Paloyan E. High phosphate diet-induced primary hyperparathyroidism: An animal model Surgery 1991 110 1745975
  22. [22]Richter B. Kapanadze T. Weingärtner N. Walter S. Vogt I. Grund A. Schmitz J. Bräsen J.H. Limbourg F.P. Haffner D. High phosphate-induced progressive proximal tubular injury is associated with the activation of Stat3/Kim-1 signaling pathway and macrophage recruitment Faseb J. 2022 36 e22407 10.1096/fj.202200167RR 35713543 · DOI
  23. [23]Latic N. Zupcic A. Frauenstein D. Erben R.G. Activation of RAAS Signaling Contributes to Hypertension in Aged Hyp Mice Biomedicines 2022 10 1691 10.3390/biomedicines10071691 35884995 PMC9313116 · DOI
  24. [24]Andrukhova O. Slavic S. Zeitz U. Riesen S.C. Heppelmann M.S. Ambrisko T.D. Markovic M. Kuebler W.M. Erben R.G. Vitamin D Is a Regulator of Endothelial Nitric Oxide Synthase and Arterial Stiffness in Mice Mol. Endocrinol. 2014 28 53 64 10.1210/me.2013-1252 24284821 PMC5426652 · DOI
  25. [25]Peitzsch M. Pelzel D. Glöckner S. Prejbisz A. Fassnacht M. Beuschlein F. Januszewicz A. Siegert G. Eisenhofer G. Simultaneous liquid chromatography tandem mass spectrometric determination of urinary free metanephrines and catecholamines, with comparisons of free and deconjugated metabolites Clin. Chim. Acta 2013 418 50 58 10.1016/j.cca.2012.12.031 23313054 · DOI
  26. [26]Kollenkirchen U. Fox J. Walters M.R. Normocalcemia without hyperparathyroidism in vitamin D-deficient rats J. Bone Miner. Res. 1991 6 273 278 10.1002/jbmr.5650060309 2035354 · DOI
  27. [27]Hu M.C. Shi M. Cho H.J. Adams-Huet B. Paek J. Hill K. Shelton J. Amaral A.P. Faul C. Taniguchi M. Klotho and Phosphate Are Modulators of Pathologic Uremic Cardiac Remodeling J. Am. Soc. Nephrol. 2015 26 1290 1302 10.1681/ASN.2014050465 25326585 PMC4446876 · DOI
  28. [28]Grabner A. Schramm K. Silswal N. Hendrix M. Yanucil C. Czaya B. Singh S. Wolf M. Hermann S. Stypmann J. FGF23/FGFR4-mediated left ventricular hypertrophy is reversible Sci. Rep. 2017 7 1993 10.1038/s41598-017-02068-6 28512310 PMC5434018 · DOI
  29. [29]Fantin F. Mattocks A. Bulpitt C.J. Banya W. Rajkumar C. Is augmentation index a good measure of vascular stiffness in the elderly? Age Ageing 2006 36 43 48 10.1093/ageing/afl115 17114200 · DOI
  30. [30]Blacher J. Safar M.E. Large-artery stiffness, hypertension and cardiovascular risk in older patients Nat. Clin. Pract. Cardiovasc. Med. 2005 2 450 455 10.1038/ncpcardio0307 16265585 · DOI
  31. [31]Safar M.E. Arterial stiffness as a risk factor for clinical hypertension Nat. Rev. Cardiol. 2017 15 97 105 10.1038/nrcardio.2017.155 29022570 · DOI
  32. [32]Radloff J. Latic N. Pfeiffenberger U. Schüler C. Tangermann S. Kenner L. Erben R.G. A phosphate and calcium-enriched diet promotes progression of 5/6-nephrectomy-induced chronic kidney disease in C57BL/6 mice Sci. Rep. 2021 11 14868 10.1038/s41598-021-94264-8 34290280 PMC8295299 · DOI
  33. [33]Mahmud A. Feely J. Review: Arterial stiffness and the renin-angiotensin-aldosterone system J. Renin-Angiotensin-Aldosterone Syst. 2004 5 102 108 10.3317/jraas.2004.025 15526244 · DOI
  34. [34]Bühler F.R. Laragh J.H. Baer L. Vaughan E.D. Brunner H.R. Propranolol Inhibition of Renin Secretion N. Engl. J. Med. 1972 287 1209 1214 10.1056/NEJM197212142872401 5084985 · DOI
  35. [35]Miller A.J. Arnold A.C. The renin–angiotensin system in cardiovascular autonomic control: Recent developments and clinical implications Clin. Auton. Res. 2018 29 231 243 10.1007/s10286-018-0572-5 30413906 PMC6461499 · DOI
  36. [37]Tanaka H. Safar M.E. Influence of lifestyle modification on arterial stiffness and wave reflections* Am. J. Hypertens. 2005 18 137 144 10.1016/j.amjhyper.2004.07.008 15691628 · DOI
  37. [38]Kaess B.M. Rong J. Larson M.G. Hamburg N.M. Vita J.A. Levy D. Benjamin E.J. Vasan R.S. Mitchell G.F. Aortic Stiffness, Blood Pressure Progression, and Incident Hypertension JAMA 2012 308 875 881 10.1001/2012.jama.10503 22948697 PMC3594687 · DOI
  38. [39]Martínez-Moreno J.M. Herencia C. de Oca Addy M. Díaz-Tocados J.M. Vergara N. Gómez-Luna M.J. López-Argüello S.D. Camargo A. Peralbo-Santaella E. Rodríguez-Ortiz M.E. High phosphate induces a pro-inflammatory response by vascular smooth muscle cells and modulation by vitamin D derivatives Clin. Sci. 2017 131 1449 1463 10.1042/CS20160807 28442557 · DOI
  39. [40]Andreis D.T. Singer M. Catecholamines for inflammatory shock: A Jekyll-and-Hyde conundrum. Intensiv Care Med. 2016 42 1387 1397 10.1007/s00134-016-4249-z 26873833 · DOI
  40. [41]Parasiliti-Caprino M. Obert C. Lopez C. Bollati M. Bioletto F. Bima C. Egalini F. Berton A. Prencipe N. Settanni F. Association of Urine Metanephrine Levels with CardiometaBolic Risk: An Observational Retrospective Study J. Clin. Med. 2021 10 1967 10.3390/jcm10091967 34064307 PMC8125207 · DOI
  41. [42]Grouzmann E. Lamine F. Determination of catecholamines in plasma and urine Best Pract. Res. Clin. Endocrinol. Metab. 2013 27 713 723 10.1016/j.beem.2013.06.004 24094641 · DOI
  42. [44]Coulson J.M. The relationship between blood pressure variability and catecholamine metabolites: A pilot study J. Hum. Hypertens. 2014 29 50 52 10.1038/jhh.2014.23 24694800 · DOI
  43. [45]Freundlich M. Gamba G. Rodriguez-Iturbe B. Fibroblast growth factor 23—Klotho and hypertension: Experimental and clinical mechanisms Pediatr. Nephrol. 2020 36 3007 3022 10.1007/s00467-020-04843-6 33230698 PMC7682775 · DOI
  44. [46]Pi M. Ye R. Han X. Armstrong B. Liu X. Chen Y. Sun Y. Quarles L.D. Cardiovascular Interactions between Fibroblast Growth Factor-23 and Angiotensin II Sci. Rep. 2018 8 12398 10.1038/s41598-018-30098-1 30120363 PMC6098163 · DOI
  45. [47]Dai B. David V. Martin A. Huang J. Li H. Jiao Y. Gu W. Quarles L.D. A Comparative Transcriptome Analysis Identifying FGF23 Regulated Genes in the Kidney of a Mouse CKD Model PLoS ONE 2012 7 e44161 10.1371/journal.pone.0044161 22970174 PMC3435395 · DOI
  46. [48]Dörr K. Kammer M. Reindl-Schwaighofer R. Lorenz M. Marculescu R. Poglitsch M. Beitzke D. Oberbauer R. The Effect of FGF23 on Cardiac Hypertrophy Is Not Mediated by Systemic Renin-Angiotensin- Aldosterone System in Hemodialysis Front. Med. 2022 9 10.3389/fmed.2022.878730 PMC9086596 35559350 · DOI
  47. [49]Oshima N. Onimaru H. Yamagata A. Ito S. Imakiire T. Kumagai H. Rostral ventrolateral medulla neuron activity is suppressed by Klotho and stimulated by FGF23 in newborn Wistar rats Auton. Neurosci. 2020 224 102640 10.1016/j.autneu.2020.102640 32036244 · DOI
  48. [50]Kawai M. Kinoshita S. Shimba S. Ozono K. Michigami T. Sympathetic Activation Induces Skeletal Fgf23 Expression in a Circadian Rhythm-dependent Manner J. Biol. Chem. 2014 289 1457 1466 10.1074/jbc.M113.500850 24302726 PMC3894328 · DOI

Cited by

Sorted by citations

Authors
Latic, N., Peitzsch, M., Zupcic, A., Pietzsch, J., & Erben, R. G.
Affiliations
  • University of Veterinary Medicine Vienna (AT)
  • University Hospital Carl Gustav Carus (DE)
  • Helmholtz-Zentrum Dresden-Rossendorf (DE)
Corresponding author
Erben, Reinhold G.
ORCID
Venue
Biomedicines
Publisher
MDPI AG
Published
2022-10-07
Volume
10
Issue
10
Pages
2510
ISSN
2227-9059 (ISSN-L)
DOI
10.3390/biomedicines10102510
PMC
PMC9599363
OpenAlex
W4303614130
Cited by
14
References
2
Citations by year
2026: 4 · 2025: 5 · 2024: 3 · 2023: 2
FWCI
1.59
Type
journal article
Language
en
Open access
Licence
Locations
  • Biomedicines (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Collaborative Research Center Transregio 205 “The Adrenal: Central Relay in Health and Disease” (CRC/TRR 205/1,2)
  • Open Access Funding by the University of Veterinary Medicine Vienna (CRC/TRR 205/1,2)
Topics
  • Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
Keywords
dietary phosphorus, arterial blood pressure, renin-angiotensin-aldosterone system, sympathetic nervous system, fibroblast growth factor 23, left ventricular hypertrophy, catecholamines, urinary aldosterone, secondary hyperparathyroidism, calcium and phosphorus balance, mice, dietary calcium restriction, metanephrine

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review