FGF23 and Klotho Levels are Independently Associated with Diabetic Foot Syndrome in Type 2 Diabetes Mellitus

  1. Tagua, Víctor
  2. Cerro-López, Purificación
  3. López-Castillo, Ángel
  4. Donate-Correa, Javier
  5. Delgado-Molinos, Alejandro
  6. Arévalo-González, Miguel
  7. Hernández-Carballo, Carolina
  8. Martín-Núñez, Ernesto
  9. López-Tarruella, Victoria
  10. Rodríguez-Ramos, Sergio
  11. Ferri, Carla
  12. Pérez-Delgado, Nayra
  13. Mora-Fernández, Carmen
  14. Navarro-González, Juan
  1. 1 Hospital Universitario Nuestra Señora de Candelaria
    info

    Hospital Universitario Nuestra Señora de Candelaria

    Santa Cruz de Tenerife, España

    ROR https://ror.org/005a3p084

Revista:
Journal of Clinical Medicine

ISSN: 2077-0383

Año de publicación: 2019

Volumen: 8

Número: 4

Páginas: 448

Tipo: Artículo

DOI: 10.3390/JCM8040448 GOOGLE SCHOLAR lock_openAcceso abierto editor

Otras publicaciones en: Journal of Clinical Medicine

Objetivos de desarrollo sostenible

Resumen

Background: Diabetic foot syndrome (DFS) is a prevalent complication in the diabetic population and a major cause of hospitalizations. Diverse clinical studies have related alterations in the system formed by fibroblast growth factor (FGF)-23 and Klotho (KL) with vascular damage. In this proof-of-concept study, we hypothesize that the levels of FGF23 and Klotho are altered in DFS patients. Methods: Twenty patients with limb amputation due to DFS, 37 diabetic patients without DFS, and 12 non-diabetic cadaveric organ donors were included in the study. Serum FGF23/Klotho and inflammatory markers were measured by enzyme-linked immunosorbent assay (ELISA). Protein and gene expression levels in the vascular samples were determined by immunohistochemistry and quantitative real-time PCR, respectively. Results: Serum Klotho is significantly reduced and FGF23 is significantly increased in patients with DFS (p < 0.01). Vascular immunoreactivity and gene expression levels for Klotho were decreased in patients with DFS (p < 0.01). Soluble Klotho was inversely related to serum C-reactive protein (r = −0.30, p < 0.05). Vascular immunoreactivities for Klotho and IL6 showed an inverse association (r = −0.29, p < 0.04). Similarly, vascular gene expression of KL and IL6 were inversely associated (r = −0.31, p < 0.05). Logistic regression analysis showed that higher Klotho serum concentrations and vascular gene expression levels were related to a lower risk of DFS, while higher serum FGF23 was associated with a higher risk for this complication. Conclusion: FGF23/Klotho system is associated with DFS, pointing to a new pathophysiological pathway involved in the development and progression of this complication.

Referencias bibliográficas

  • International Diabetes Federation. IDF Diabetes Atlas, 8th ed.; International Diabetes Federation: Brussels, Belgium, 2017. [Google Scholar] Bild, D.E.; Selby, J.V.; Sinnock, P.; Browner, W.S.; Braveman, P.; Showstack, J.A. Lower-extremity amputation in people with diabetes. Epidemiology and prevention. Diabetes Care 1989, 12, 24–31. [Google Scholar] [CrossRef]
  • Armstrong, D.G.; Wrobel, J.; Robbins, J.M. Guest Editorial: Are diabetes-related wounds and amputations worse than cancer? Int. Wound J. 2007, 4, 286–287. [Google Scholar] [PubMed]
  • Ross, R. Atherosclerosis—An inflammatory disease. N. Engl. J. Med. 1999, 340, 115–126. [Google Scholar] [CrossRef] [PubMed]
  • van der Wal, A.C.; Becker, A.E.; van der Loos, C.M.; Das, P.K. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 1994, 89, 36–44. [Google Scholar] [CrossRef]
  • Navarro-González, J.F.; Mora-Fernández, C.; Muros de Fuentes, M.; Donate-Correa, J.; Cazaña-Pérez, V.; García-Pérez, J. Effect of phosphate binders on serum inflammatory profile, soluble CD14, and endotoxin levels in hemodialysis patients. Clin. J. Am. Soc. Nephrol. 2011, 6, 2272–2279. [Google Scholar] [CrossRef] [PubMed]
  • Navarro-González, J.F.; Mora-Fernández, C.; Muros, M.; Herrera, H.; García, J. Mineral metabolism and inflammation in chronic kidney disease patients: A cross−sectional study. Clin. J. Am. Soc. Nephrol. 2009, 4, 1646–1654. [Google Scholar] [CrossRef]
  • Yu, X.; Ibrahimi, O.A.; Goetz, R.; Zhang, F.; Davis, S.I.; Garringer, H.J.; Linhardt, R.J.; Ornitz, D.M.; Mohammadi, M.; White, K.E. Analysis of the biochemical mechanisms for the endocrine actions of fibroblast growth factor-23. Endocrinology 2005, 146, 4647–4656. [Google Scholar] [CrossRef]
  • Imura, A.; Iwano, A.; Tohyama, O.; Tsuji, Y.; Nozaki, K.; Hashimoto, N.; Fujimori, T.; Nabeshima, Y.-I. Secreted Klotho protein in sera and CSF: Implication for post−translational cleavage in release of Klotho protein from cell membrane. FEBS Lett. 2004, 565, 143–147. [Google Scholar] [CrossRef]
  • Akimoto, T.; Yoshizawa, H.; Watanabe, Y.; Numata, A.; Yamazaki, T.; Takeshima, E.; Iwazu, K.; Komada, T.; Otani, N.; Morishita, Y.; et al. Characteristics of urinary and serum soluble Klotho protein in patients with different degrees of chronic kidney disease. BMC Nephrol. 2012, 13, 155. [Google Scholar]
  • Matsumura, Y.; Aizama, H.; Shiraki-lida, T.; Naqai, R.; Kuro-o, M.; Nabeshima, Y. Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem Biophys. Res. Commun. 1998, 242, 626–630. [Google Scholar] [CrossRef]
  • Kanbay, M.; Nicoleta, M.; Selcoki, Y.; Ikizek, M.; Aydin, M.; Eryonucu, B.; Duranay, M.; Akcay, A.; Armutcu, F.; Covic, A. Fibroblast growth factor 23 and fetuin A are independent predictors for the coronary artery disease extent in mild chronic kidney disease. Clin. J. Am. Soc. Nephrol. 2010, 5, 1780–1786. [Google Scholar] [CrossRef] [PubMed]
  • Gutiérrez, O.M.; Mannstadt, M.; Isakova, T.; Rauh-Hain, J.A.; Tamez, H.; Shah, A.; Smith, K.; Lee, H.; Thadhani, R.; Jüppner, H.; et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N. Engl. J. Med. 2008, 359, 584–592. [Google Scholar] [CrossRef] [PubMed]
  • Faul, C.; Amaral, A.P.; Oskouei, B.; Hu, M.-C.; Sloan, A.; Isakova, T.; Gutierrez, O.M.; Aguillon-Prada, R.; Lincoln, J.; Hare, J.M.; et al. FGF23 induces left ventricular hypertrophy. J. Clin. Investig. 2011, 121, 4393–4408. [Google Scholar] [CrossRef][Green Version]
  • Mirza, M.A.; Larsson, A.; Lind, L.; Larsson, T.E. Circulating fibroblast growth factor-23 is associated with vascular dysfunction in the community. Atherosclerosis 2009, 205, 385–390. [Google Scholar] [CrossRef]
  • Lim, K.; Lu, T.S.; Molostvov, G.; Lee, C.; Lam, F.T.; Zehnder, D.; Hsiao, L.L. Vascular Klotho deficiency potentiates the development of human artery calcification and mediates resistance to FGF-23. Circulation 2012, 125, 2243–2255. [Google Scholar] [CrossRef] [PubMed]
  • Hu, M.C.; Kuro-o, M.; Moe, O.W. Renal and extrarenal actions of Klotho. Semin. Nephrol. 2013, 33, 118–129. [Google Scholar] [CrossRef]
  • Donate-Correa, J.; Mora-Fernández, C.; Martínez-Sanz, R.; Muros-De-Fuentes, M.; Perez, H.; Meneses-Pérez, B.; Cazaña-Pérez, V.; Navarro-Gonzalez, J.F. Expression of FGF23/KLOTHO system in human vascular tissue. Int. J. Cardiol. 2013, 165, 179–183. [Google Scholar] [CrossRef] [PubMed]
  • Martín-Núñez, E.; Donate-Correa, J.; López-Castillo, Á.; Delgado-Molinos, A.; Ferri, C.; Rodríguez-Ramos, S.; Cerro, P.; Pérez-Delgado, N.; Castro, V.; Hernández-Carballo, C.; et al. Soluble levels and endogenous vascular gene expression of KLOTHO are related to inflammation in human atherosclerotic disease. Clin. Sci. (Lond.) 2017, 131, 2601–2609. [Google Scholar] [CrossRef]
  • Donate-Correa, J.; Martín-Núñez, E.; Martínez-Sanz, R.; Muros-de-Fuentes, M.; Mora-Fernández, C.; Pérez-Delgado, N.; Navarro-González, J.F. Influence of Klotho gene polymorphisms on vascular gene expression and its relationship to cardiovascular disease JF. J. Cell Mol. Med. 2016, 20, 128–133. [Google Scholar] [CrossRef]
  • Navarro-González, J.F.; Donate-Correa, J.; Muros de Fuentes, M.; Pérez-Hernández, H.; Martínez-Sanz, R.; Mora-Fernández, C. Reduced Klotho is associated with the presence and severity of coronary artery disease. Heart 2014, 100, 34–40. [Google Scholar] [CrossRef] [PubMed]
  • Schaper, N.C.; Nabuurs-Franssen, M.H. The diabetic foot: Pathogenesis and clinical evaluation. Semin. Vasc. Med. 2002, 2, 221–228. [Google Scholar] [CrossRef]
  • Mirza, M.A.; Hansen, T.; Johansson, L.; Ahlström, H.; Larsson, A.; Lind, L. Relationship between circulating FGF23 and total body atherosclerosis in the community. Nephrol. Dial. Transplant. 2009, 24, 3125–3131. [Google Scholar] [CrossRef][Green Version]
  • Kuro-O, M.; Matsumura, Y.; Aizawa, H.; Suga, T.; Utsugi, T.; Ohyama, Y.; Kurabayashi, M.; Kaname, T.; Kume, E.; Iwasaki, H.; et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997, 390, 45–51. [Google Scholar] [CrossRef] [PubMed]
  • Saito, Y.; Nakamura, T.; Ohtama, Y.; Suzuki, T.; Iida, A.; Shiraki-Iida, T.; Kuro-O, M.; Nabeshima, Y.-I.; Kurabayashi, M.; Nagai, R. In vivo klotho gene delivery protects against endothelial dysfunction in multiple risk factor syndrome. Biochem. Biophys. Res. Commun. 2000, 276, 767–772. [Google Scholar] [CrossRef] [PubMed]
  • Nagai, R.; Saito, Y.; Ohyama, Y.; Aizawa, H.; Suga, T.; Nakamura, T.; Kurabayashi, M.; Kuroo, M. Endothelial dysfunction in the klotho mouse and downregulation of klotho gene expression in various animal models of vascular and metabolic diseases. Cell. Mol. Life Sci. 2000, 57, 738–746. [Google Scholar] [CrossRef] [PubMed]
  • Keles, N.; Caliskan, M.; Dogan, B.; Keles, N.N.; Kalcik, M.; Aksu, F.; Kostek, O.; Aung, S.M.; Isbilen, B.; Oguz, A. Low serum level of Klotho is an early predictor of atherosclerosis. Tohoku J. Exp. Med. 2015, 237, 17–23. [Google Scholar] [CrossRef] [PubMed]
  • Semba, R.D.; Cappola, A.R.; Sun, K.; Bandinelli, S.; Dalal, M.; Crasto, C.; Guralnik, J.M.; Ferrucci, L. Plasma klotho and cardiovascular disease. J. Am. Geriatr. Soc. 2011, 59, 1596–1601. [Google Scholar] [CrossRef]
  • 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 Complicat. 2018, 32, 922–930. [Google Scholar] [CrossRef]
  • Ruiz-Andrés, O.; Sánchez-Niño, M.D.; Moreno, J.A.; Ruiz-Ortega, M.; Ramos, A.M.; Sanz, A.B.; Ortiz, A. Downregulation of kidney protective factors by inflammation: Role of transcription factors and epigenetic mechanisms. Am. J. Physiol. Renal Physiol. 2016, 311, 1329–1340. [Google Scholar] [CrossRef]