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The antihypertensive action of C-phycocyanin is related to the prevention of angiotensin II-caused vascular dysfunction in chronic kidney disease

Abstract

C-phycocyanin (CPC) is a photosynthetic protein found in Arthrospira maxima with a nephroprotective and antihypertensive activity that can prevent the development of hemodynamic alterations caused by chronic kidney disease (CKD). However, the complete nutraceutical activities are still unknown. This study aims to determine if the antihypertensive effect of CPC is associated with preventing the impairment of hemodynamic variables through delaying vascular dysfunction. Twenty-four normotensive male Wistar rats were divided into four groups: (1) sham + 4 mL/kg/d vehicle (100 mM of phosphate buffer, PBS) administered by oral gavage (og), (2) sham + 100 mg/kg/d og of CPC, (3) CKD induced by 5/6 nephrectomy (CKD) + vehicle, (4) CKD + CPC. One week after surgery, the CPC treatment began and was administrated daily for four weeks. At the end treatment, animals were euthanized, and their thoracic aorta was used to determine the vascular function and expression of AT1, AT2, and Mas receptors. CKD-induced systemic arterial hypertension (SAH) and vascular dysfunction by reducing the vasorelaxant response of angiotensin 1–7 and increasing the contractile response to angiotensin II. Also, CKD increased the expression of the AT1 and AT2 receptors and reduced the Mas receptor expression. Remarkably, the treatment with CPC prevented SAH, renal function impairment, and vascular dysfunction in the angiotensin system. In conclusion, the antihypertensive activity of CPC is associated with avoiding changes in the expression of AT1, AT2, and Mas receptors, preventing vascular dysfunction development and SAH in rats with CKD.

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References

  1. Webster AC, Nagler EV, Morton RL, Masson P. Chronic kidney disease. Lancet. 2017;389:1238–52. https://doi.org/10.1016/S0140-6736(16)32064-5.

    Article  PubMed  Google Scholar 

  2. KDIGO. Clinical practice guideline for the management of glomerular diseases. Kidney Int. 2021;100:S1–S276.

    Article  Google Scholar 

  3. Terada Y, Yayama K. Angiotensin II-induced vasoconstriction via Rho kinase activation in pressure-overloaded rat thoracic aortas. Biomolecules. 2021;11:1076 https://doi.org/10.3390/biom11081076.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Chou Y-H, Chu T-S, Lin S-L. Role of renin-angiotensin system in acute kidney injury-chronic kidney disease transition. Nephrology. 2018;23:121–5. https://doi.org/10.1111/nep.13467.

    Article  CAS  PubMed  Google Scholar 

  5. Bader M, Alenina N, Young D, Santos RAS, Touyz RM. The meaning of mas. Hypertension. 2018;72:1072–5. https://doi.org/10.1161/HYPERTENSIONAHA.118.10918.

    Article  CAS  PubMed  Google Scholar 

  6. Nowak KL, Jovanovich A, Farmer-Bailey H, Bispham N, Struemph T, Malaczewski M, et al. Vascular dysfunction, oxidative stress, and inflammation in chronic kidney disease. Kidney360. 2020;1:501–9. https://doi.org/10.34067/kid.0000962019.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Roumeliotis S, Mallamaci F, Zoccali C. Endothelial dysfunction in chronic kidney disease, from Biology to clinical outcomes: a 2020 update. J Clin Med. 2020;9:2359 https://doi.org/10.3390/jcm9082359.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Alani H. Cardiovascular co-morbidity in chronic kidney disease: current knowledge and future research needs. World J Nephrol. 2014;3:156 https://doi.org/10.5527/wjn.v3.i4.156.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Yan M-T, Chao C-T, Lin S-H. Chronic kidney disease: strategies to retard progression. Int J Mol Sci. 2021;22:10084 https://doi.org/10.3390/ijms221810084.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Daliu P, Santini A, Novellino E. From pharmaceuticals to nutraceuticals: bridging disease prevention and management. Expert Rev Clin Pharmacol. 2019;12:1–7. https://doi.org/10.1080/17512433.2019.1552135.

    Article  CAS  PubMed  Google Scholar 

  11. Szulinska M, Gibas-Dorna M, Miller-Kasprzak E, Suliburska J, Miczke A, Walczak-Gałezewska M, et al. Spirulina maxima improves insulin sensitivity, lipid profile, and total antioxidant status in obese patients with well-treated hypertension: a randomized double-blind placebo-controlled study. Eur Rev Med Pharmacol Sci. 2017;21:2473–81.

    CAS  PubMed  Google Scholar 

  12. Ichimura M, Kato S, Tsuneyama K, Matsutake S, Kamogawa M, Hirao E, et al. Phycocyanin prevents hypertension and low serum adiponectin level in a rat model of metabolic syndrome. Nutr Res. 2013;33:397–405. https://doi.org/10.1016/j.nutres.2013.03.006.

    Article  CAS  PubMed  Google Scholar 

  13. Rojas-Franco P, Garcia-Pliego E, Vite-Aquino AG, Franco-Colin M, Serrano-Contreras JI, Paniagua-Castro N, et al. The nutraceutical antihypertensive action of C-phycocyanin in chronic kidney disease is related to the prevention of endothelial dysfunction. Nutrients. 2022;14:1464 https://doi.org/10.3390/nu14071464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Norma Oficial Mexicana NOM-062-ZOO-1999: Especificaciones técnicas para la producción, cuidado y uso de los animales de laboratorio. 1999.

  15. Memije-Lazaro IN, Blas-Valdivia V, Franco-Colín M, Cano-Europa E. Arthrospira maxima (Spirulina) and C-phycocyanin prevent the progression of chronic kidney disease and its cardiovascular complications. J Funct Foods. 2018;43:37–43. https://doi.org/10.1016/j.jff.2018.01.013.

    Article  CAS  Google Scholar 

  16. Sinha AD, Agarwal R. Clinical pharmacology of antihypertensive therapy for the treatment of hypertension in CKD. Clin J Am Soc Nephrol. 2019;14:757 https://doi.org/10.2215/CJN.04330418.

    Article  CAS  PubMed  Google Scholar 

  17. Martínez-Sámano J, Torres-Montes de Oca A, Luqueño-Bocardo OI. Torres-Durán P v, Juárez-Oropeza MA. Spirulina maxima decreases endothelial damage and oxidative stress indicators in patients with systemic arterial hypertension: results from exploratory controlled clinical trial. Mar Drugs. 2018;16:496.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Ding J, Yu M, Jiang J, Luo Y, Zhang Q, Wang S, et al. Angiotensin II decreases endothelial nitric oxide synthase phosphorylation via AT1R Nox/ROS/PP2A pathway. Front Physiol. 2020;11:566410 https://doi.org/10.3389/fphys.2020.566410.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Higashi M, Shimokawa H, Hattori T, Hiroki J, Mukai Y, Morikawa K, et al. Long-term inhibition of Rho-kinase suppresses angiotensin II-induced cardiovascular hypertrophy in rats in vivo: effect on endothelial NAD(P)H oxidase system. Circ Res. 2003;93:767–75. https://doi.org/10.1161/01.RES.0000096650.91688.28.

    Article  CAS  PubMed  Google Scholar 

  20. Roks AJM, Rodgers K, Walther T. Effects of the renin angiotensin system on vasculogenesis-related progenitor cells. Curr Opin Pharmacol. 2011;11:162–74. https://doi.org/10.1016/j.coph.2011.01.002.

    Article  CAS  PubMed  Google Scholar 

  21. Zhang M-Z, Yao B, Cheng H-F, Wang S-W, Inagami T, Harris RC. Renal cortical cyclooxygenase 2 expression is differentially regulated by angiotensin II AT1 and AT2 receptors. Proc Natl Acad Sci USA. 2006;103:16045–50. https://doi.org/10.1073/pnas.0602176103.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cermeño M, Stack J, Tobin PR, O’Keeffe MB, Harnedy PA, Stengel DB, et al. Peptide identification from a Porphyra dioica protein hydrolysate with antioxidant, angiotensin converting enzyme and dipeptidyl peptidase IV inhibitory activities. Food Funct. 2019;10:3421–9. https://doi.org/10.1039/C9FO00680J.

    Article  PubMed  Google Scholar 

  23. Pan F, Zhou N, Li J, Du X, Zhao L, Wang C, et al. Identification of c-phycocyanin-derived peptides as angiotensin converting enzyme and dipeptidyl peptidase IV inhibitors via molecular docking and molecular dynamic simulation. ES Food Agroforestry. 2020;2:58–69. https://doi.org/10.30919/esfaf1116.

    Article  Google Scholar 

  24. Blas-Valdivia V, Moran-Dorantes DN, Rojas-Franco P, Franco-Colin M, Mirhosseini N, Davarnejad R, et al. C-Phycocyanin prevents acute myocardial infarction-induced oxidative stress, inflammation and cardiac damage. Pharm Biol. 2022;60:755–63. https://doi.org/10.1080/13880209.2022.2055089.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zheng J, Inoguchi T, Sasaki S, Maeda Y, McCarty MF, Fujii M, et al. Phycocyanin and phycocyanobilin from Spirulina platensis protect against diabetic nephropathy by inhibiting oxidative stress. Am J Physiol Regul Integr Comp Physiol. 2013;304:R110 LP–R120. https://doi.org/10.1152/ajpregu.00648.2011.

    Article  CAS  Google Scholar 

  26. Reddy CM, Bhat VB, Kiranmai G, Reddy MN, Reddanna P, Madyastha KM. Selective inhibition of cyclooxygenase-2 by C-phycocyanin, a biliprotein from Spirulina platensis. Biochem Biophys Res Commun. 2000;277:599–603. https://doi.org/10.1006/bbrc.2000.3725.

    Article  CAS  PubMed  Google Scholar 

  27. Jiang L, Wang Y, Yin Q, Liu G, Liu H, Huang Y, et al. Phycocyanin: a potential drug for cancer treatment. J Cancer. 2017;8:3416. https://doi.org/10.7150/jca.21058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hannan RE, Davis EA, Widdop RE. Functional role of angiotensin II AT2 receptor in modulation of AT1 receptor-mediated contraction in rat uterine artery: involvement of bradykinin and nitric oxide. Br J Pharmacol. 2003;140:987–95. https://doi.org/10.1038/sj.bjp.0705484.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yayama K, Okamoto H. Angiotensin II-induced vasodilation via type 2 receptor: role of bradykinin and nitric oxide. Int Immunopharmacol. 2008;8:312–8. https://doi.org/10.1016/j.intimp.2007.06.012.

    Article  CAS  PubMed  Google Scholar 

  30. Brassard P, Amiri F, Schiffrin EL. Combined angiotensin II type 1 and type 2 receptor blockade on vascular remodeling and matrix metalloproteinases in resistance arteries. Hypertension. 2005;46:598–606. https://doi.org/10.1161/01.HYP.0000176744.15592.7d.

    Article  CAS  PubMed  Google Scholar 

  31. Chassagne C, Adamy C, Ratajczak P, Gingras B, Teiger E, Planus E, et al. Angiotensin II AT2 receptor inhibits smooth muscle cell migration via fibronectin cell production and binding. Am J Physiol Cell Physiol. 2002;282:C654–64. https://doi.org/10.1152/ajpcell.00318.2001.

    Article  CAS  PubMed  Google Scholar 

  32. Murugan D, Lau YS, Lau CW, Mustafa MR, Huang Y. Angiotensin 1-7 protects against angiotensin II-induced endoplasmic reticulum stress and endothelial dysfunction via Mas receptor. PLoS One. 2015;10:e0145413 https://doi.org/10.1371/journal.pone.0145413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Dilauro M, Zimpelmann J, Robertson SJ, Genest D, Burns KD. Effect of ACE2 and angiotensin-(1–7) in a mouse model of early chronic kidney disease. Am J Physiol Renal Physiol. 2010;298:F1523–F1532. https://doi.org/10.1152/ajprenal.00426.2009.

    Article  CAS  PubMed  Google Scholar 

  34. Rabelo LA, Alenina N, Bader M. ACE2-angiotensin-(1-7)-Mas axis and oxidative stress in cardiovascular disease. Hypertens Res. 2011;34:154–60. https://doi.org/10.1038/hr.2010.235.

    Article  CAS  PubMed  Google Scholar 

  35. Satirapoj B, Supasyndh O, Nata N, Phulsuksombuti D, Utennam D, Kanjanakul I, et al. High levels of uric acid correlate with decline of glomerular filtration rate in chronic kidney disease. J Med Assoc Thai. 2010;93:S65–70.

    PubMed  Google Scholar 

  36. Mazzali M, Hughes J, Kim YG, Jefferson JA, Kang DH, Gordon KL, et al. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension. 2001;38:1101–6. https://doi.org/10.1161/hy1101.092839.

    Article  CAS  PubMed  Google Scholar 

  37. Rojas-Franco P, Franco-Colín M, Blas-Valdivia V, Melendez-Camargo ME, Cano-Europa E. Arthrospira maxima (Spirulina) prevents endoplasmic reticulum stress in the kidney through its C-phycocyanin. J Zhejiang Univ Sci B. 2021;22:603–8. https://doi.org/10.1631/jzus.B2000725.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rodríguez-Sánchez R, Ortiz-Butrón R, Blas-Valdivia V, Hernández-García A, Cano-Europa E. Phycobiliproteins or C-phycocyanin of Arthrospira (Spirulina) maxima protect against HgCl2-caused oxidative stress and renal damage. Food Chem. 2012;135:2359–65. https://doi.org/10.1016/j.foodchem.2012.07.063.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank INSTITUTO POLITÉCNICO NACIONAL, SECRETARÍA DE INVESTIGACIÓN Y POSGRADO-IP, and CONACyT-Mexico for financial support. The researchers are fellows of EDI, COFAA, and SNI. In addition, the study was supported by SIP-IPN (20221728, 20221521, 20221801, 20221745) and CONACyT-Mexico (Grant No: CB-252702). The datasets generated during the current study are available from the corresponding author upon reasonable request.

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Correspondence to Vanessa Blas-Valdivia or Edgar Cano-Europa.

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Tapia-Martínez, J.A., Centurión, D., Franco-Colin, M. et al. The antihypertensive action of C-phycocyanin is related to the prevention of angiotensin II-caused vascular dysfunction in chronic kidney disease. Hypertens Res 47, 1024–1032 (2024). https://doi.org/10.1038/s41440-023-01572-9

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