KLOTHO PROTEIN, FIBROBLAST GROWTH FACTOR 23 AND RENAL CALCIUM EXCRETION IN INITIAL STAGES OF EXPERIMENTAL CHRONIC KIDNEY DISEASE

INTRODUCTION. It is suggested that fibroblast growth factor 23 (FGF23) and its co-receptor Klotho are probably associated
with changes in calcium metabolism in chronic kidney disease (CKD) due to ability to regulate intracellular Ca transport by
modulating the cationic channels TRPV5 and TRPV6.

THE AIM is to investigate the association between Klotho, FGF23 and renal excretion of Ca in the initial stages of experimental CKD.

MATERIAL AND METHODS. The experimental models of chronic kidney injury were resection of the renal tissue in spontaneously hypertensive rats (SHR). Serum concentrations of intact FGF23 and PTH were determined by ELISA, renal Klotho protein expression by IHC. The indices of Ca excretion were calculated.

RESULTS. Serum creatinine concentration, creatinine clearance and the severity of interstitial fibrosis in experimental models corresponded to the initial stages of chronic kidney disease. UCa24 and FECa were higher, Klotho protein expression was lower in groups with more severe renal dysfunction, without significant differences in FGF23 and PTH levels. Multiple regression analysis showed that FECa and UCa24 were not associated with FGF23, Klotho, and PTH.

CONCLUSION. Renal excretion of Ca in initial stages of experimental kidney damage is not associated with Klotho and FGF23 levels.

1. Kuro-o M, Matsumura Y, Aizawa H et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997;390:45–51. Doi: 10.1038/36285

2. Imura A, Iwano A, Tohyama O et al. 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. Doi: 10.1016/j.febslet.2004.03.090

3. Matsumura Y, Aizawa H, Shiraki-Iida T et al. Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem Biophys Res Commun 1998;242:626–630. Doi: 10.1006/bbrc.1997.8019

4. Lindberg K, Amin R, Moe OW et al. The kidney is the principal organ mediating klotho effects. J Am Soc Nephrol 2014;25:2169–2175. Doi: 10.1681/ASN.2013111209

5. Van Husen M, Fischer AK, Lehnhardt A et al. Fibroblast growth factor 23 and bone metabolism in children with chronic kidney disease. Kidney Int 2010;78:200–206. Doi: 10.1038/ki.2010.107

6. Andrukhova O, Smorodchenko A, Egerbacher M et al. FGF23 promotes renal calcium reabsorption through the TRPV5 channel. EMBO J 2014;33:229–246. Doi: 10.1002/embj.201284188

7. Alexander Grabner, Karla Schramm, Neerupma Silswal et al. FGF23/FGFR4-mediated left ventricular hypertrophy is reversible. Sci Rep 2017; 7: 1993. Doi: 10.1038/s41598-017-02068-6

8. Takahashi S, Okada K, Nagura Y et al. Three-quarters nephrectomy in rats as a model of early renal failure. Jpn J Nephrol 1991;33(1):27–31. Doi: 10.14842/jpnjnephrol1959.33.27

9. Beresneva ON, Parastaeva MM, Ivanova GT et al. Аssessment of cardioprotective effects of low-protein soy diet and level of nonorganic anions of blood serum in spontaneously hypertensive rats. Nephrology (Saint-Petersburg) 2007;11(3):70–76

10. Huang CL. Regulation of ion channels by secreted Klotho. Adv Exp Med Biol 2012;728:100–106. Doi: 10.1007/978-1-4614-0887-1_7

11. Isakova T, Wahl P, Vargas GS et al. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int 2011;79(12):1370–1378. Doi: 10.1038/ki.2011.47

12. Armbrecht HJ, Wongsurawat N, Zenser TV, Davis BB. Effect of PTH and 1,25(OH)2D3 on renal 25(OH)D3 metabolism, adenylate cyclase, and protein kinase. Am J Physiol 1984;246(1 Pt 1):102–107. Doi: 10.1152/ajpendo.1984.246.1.E102

13. Johnson JA, Kumar R. Vitamin D and renal calcium transport. Current Opinion in Nephrology and Hypertension 1994;3(4):424–429

14. Kurosu H, Yamamoto M, Clark JD et al. Suppression of aging in mice by the hormone Klotho. Science 2005; 309:1829–1833. Doi: 10.1126/science.1112766

15. Xu Y, Sun Z. Molecular basis of Klotho: from gene to function in aging. Endocr Rev 2015; 36:174–193. Doi: 10.1210/er.2013-1079

16. Cha SK, Ortega B, Kurosu H, et al. Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin1. Proc Natl Acad Sci USA 2008; 105:9805–9810. Doi: 10.1073/pnas.0803223105

17. Tohyama O, Imura A, Iwano A, et al. Klotho is a novel betaglucuronidase capable of hydrolyzing steroid beta-glucuronides. J Biol Chem 2004;279:9777–9784. Doi: 10.1074/jbc.M312392200

18. Hu MC, Shi M, Zhang J, et al. Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J 2010;24:3438–3450. Doi: 10.1096/fj.10-154765

19. Chang Q, Hoefs S, Van Der Kemp AW, et al. The betaglucuronidase Klotho hydrolyzes and activates the TRPV5 channel. Science 2005;310:490–493. Doi: 10.1126/science.1114245

20. Huang CL. Regulation of ion channels by secreted Klotho. Adv Exp Med Biol. 2012; 728:100–106. Doi:10.1007/978-1-4614-0887-1_7

21. Andrukhova O, Bayer J, Schüler C et al. Klotho Lacks an FGF23-Independent Role in Mineral Homeostasis. JBMR 2017;32(10):2049–2061. Doi: 10.1002/jbmr.3195