Serum levels of Klotho protein in men with arterial hypertension and its association with cardiometabolic risk factors

Aim. To study serum levels of Klotho protein in men with arterial hypertension and to explore its association with some cardiometabolic risk factors.

Methods. 134 men with hypertension aged 50-65 years old and over 80 years old were enrolled in a study. 44 men of the corresponding age without high blood pressure were enrolled in the control group. Serum levels of Klotho protein were measured using ELISA.

Results. Both, the study and the control group, have similar serum levels of Klotho protein (464 [287; 849] and 458 [128; 1121] pg/dL, respectively; p>0.05). Significant differences in the serum levels of Klotho protein in the study groups are related to three risk factors: physical inactivity, obesity, and the presence of diabetes mellitus. A positive correlation between Klotho protein levels and regular physical activity has been found in men with arterial hypertension. Besides, negative correlations between Klotho proteins and diabetes mellitus and obesity have been stated. Multivariate analysis reports a positive association between Klotho protein and regular physical activity in men with hypertension regardless of their age, diabetes, lipid disorders, and obesity.

Conclusion. Men with arterial hypertension and without it have similar Klotho protein levels. Serum Klotho protein levels are lower in obese men who are physically inactive. Klotho protein levels are lower in men with hypertension and concomitant diabetes mellitus. Klotho protein is positively associated with regular physical activity regardless of age and some cardiometabolic risk factors in men with arterial hypertension.

1. Erina A.M., Rotar' O.P., Solncev V.N., Shal'nova S.A., Deev A.D., Baranova E.I., Konradi A.O., Bojcov S.A., Shljahto E.V. Jepidemiologija arterial'noj gipertenzii v Rossijskoj Federacii - vazhnost' vybora kriteriev diagnostiki. Kardiologija. 2019;59(6):5-11. doi: 10.18087/cardio.2019.6.2595 (In Russian)

2. Makarov S.A., Maksimov S.A., Shapovalova E.B., Stryapchev D.S., Artamonova G.V. Mortality from circulatory system diseases in the Kemerovo region and the russian federation in 2000-2016. Complex Issues of Cardiovascular Diseases. 2019;8(2):6-11. doi: 10.17802/2306-1278-2019-8-26-11 (In Russian)

3. Kearney P.M., Whelton M., Reynolds K., Muntner P., Whelton P.K., He J. Global burden of hypertension: analysis of worldwide data. Lancet. 2005; 365: 217-223. doi:10.1016/S0140-6736(05)17741-1.

4. Chazova I.E., Zhernakova Ju.V. ot imeni jekspertov. Klinicheskie rekomendacii. Diagnostika i lechenie arterial'noj gipertonii. Sistemnye gipertenzii. 2019; 16 (1): 6-31. doi: 10.26442/2075082X.2019.1.190179 (In Russian)

5. Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi H., Suga T., Utsugi T., Ohyama Y., Kurabayashi M., Kaname T., Kume E., Iwasaki H., Iida A., Shiraki-Iida T., Nishikawa S., Nagai R., Nabeshima Y.I. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997; 390: 45-51. doi:10.1038/36285.

6. Takenaka T., Watanabe Y., Inoue T., Miyazaki T., Suzuki H. Fibroblast growth factor 23 enhances renal klotho abundance. Pflugers Arch. 2013;465:935-943. doi: 10.1007/s00424-013-1226-z.

7. Takenaka T., Inoue T., Miyazaki T., Hayashi M., Suzuki H. Xeno-klotho inhibits parathyroid hormone signaling. J Bone Miner Res. 2016;31:455-462. doi: 10.1002/jbmr.2691.

8. Doi S., Zou Y., Togao O., Pastor J.V., John G.B., Wang L., Shiizaki K., Gotschall R., Schiavi S., Yorioka N., Takahashi M., Boothman D.A., Kuro-o M. Klotho inhibits transforming growth factor-beta1 (TGF-beta1) signaling and suppresses renal fibrosis and cancer metastasis in mice. J Biol Chem. 2011; 286:8655-8665. doi: 10.1074/jbc.M110.174037.

9. Takenaka T., Kobori H., Miyazaki T., Suzuki H., Nishiyama A., Ishii N., Yamashita M., Hayashi M. Klotho protein supplementation reduces blood pressure and renal hypertrophy in db/db mice, a model of type 2 diabetes. Acta Physiol (Oxf). 2019; 225(2):e13190. doi: 10.1111/apha.13190.

10. Takenaka T., Inoue T., Miyazaki T., Kobori H., Nishiyama A., Ishii N., Hayashi M., Suzuki H. Klotho suppresses the reninangiotensin system in adriamycin nephropathy. Nephrol Dial Transplant. 2017;32:791-800. doi: 10.1093/ndt/gfw340.

11. Chung C.P., Chang Y.C., Ding Y., Lim K., Liu Q., Zhu L., Zhang W., Lu T.S., Molostvov G., Zehnder D., Hsiao L.L. a-Klotho expression determines nitric oxide synthesis in response to FGF-23 in human aortic endothelial cells. PLoS One. 2017;12(5):e0176817. doi: 10.1371/journal.pone.0176817.

12. Park M.Y., Herrmann S.M., Saad A., Eirin A.., Tang H, Lerman A., Textor S.C., Lerman L.O.. Biomarkers of kidney injury and klotho in patients with atherosclerotic renovascular disease. Clin J Am Soc Nephrol. 2015;10(3):443-51

13. Kitagawa M., Sugiyama H., Morinaga H., Inoue T., Takiue K., Ogawa A., Yamanari T., Kikumoto Y., Uchida H.A., Kitamura S., Maeshima Y., Nakamura K., Ito H., Makino H. A decreased level of serum soluble Klotho is an independent biomarker associated with arterial stiffness in patients with chronic kidney disease. PLoS One. 2013; 8(2): e56695. doi: 10.1371/journal.pone.0056695.

14. Amaro-Gahete F.J., de-la-O A., Jurado-Fasoli L., Gutierrez A., Ruiz J.R., Castillo M.J. Association of physical activity and fitness with S-Klotho plasma levels in middleaged sedentary adults: The FIT-AGEING study. Maturitas. 2019;123:25-31. doi: 10.1016/j.maturitas.

15. Tan S.J., Chu M.M., Toussaint N.D., Cai M.M., Hewitson T.D., Holt S.G. High-intensity physical exercise increases serum a-klotho levels in healthy volunteers. J Circ Biomark. 2018; 7: 1849454418794582. doi: 10.1177/1849454418794582

16. Amaro-Gahete F.J., Jurado-Fasoli L., Sanchez-Delgado G., Garci'a-Lario J.V., Castillo M.J., Ruiz JR. Relationship between plasma S-Klotho and cardiometabolic risk in sedentary adults. Aging (Albany NY). 2020;12(3):2698-2710. doi:10.18632/aging.102771.

17. Somm E., Henry H., Bruce S.J., Aeby S., Rosikiewicz M., Sykiotis G.P., Asrih M., Jornayvaz F.R., Denechaud P.D., Albrecht U., Mohammadi M., Dwyer A., Acierno J.S. Jr., Schoonjans K., Fajas L., Greub G., Pitteloud N. в—Klotho deficiency protects against obesity through a crosstalk between liver, microbiota, and brown adipose tissue. JCI Insight. 2017;2(8):e91809. doi:10.1172/jci.insight.91809

18. Amitani M., Asakawa A., Amitani H., Kaimoto K., Sameshima N., Koyama K.I., Haruta I., Tsai M., Nakahara T., Ushikai M., Cheng K.-C., Hamada S., Inui A. Plasma klotho levels decrease in both anorexia nervosa and obesity. Nutrition. 2013; 29(9):1106-1109. doi.org/10.1016/j.nut.2013.02.005.

19. Zhang L., Liu T. Clinical implication of alterations in serum Klotho levels in patients with type 2 diabetes mellitus and its associated complications. J Diabetes Complications. 2018; 32(10): 922-930. doi: 10.1016/j.jdiacomp.2018.06.002.