Chronic hyperphosphatemia and vascular calcification are reduced by stable delivery of soluble klotho

Julia M. Hum, Linda M. O'Bryan, Arun K. Tatiparthi, Taryn A. Cass, Erica L. Clinkenbeard, Martin S. Cramer, Manoj Bhaskaran, Robert L. Johnson, Jonathan M. Wilson, Rosamund C. Smith, Kenneth E. White

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28 Scopus citations


αKlotho (αKL) regulates mineral metabolism, and diseases associated with αKL deficiency are characterized by hyperphosphatemia and vascular calcification (VC). αKL is expressed as a membrane-bound protein (mKL) and recognized as the coreceptor for fibroblast growth factor-23 (FGF23) and a circulating soluble form (cKL) created by endoproteolytic cleavage ofmKL. The functions of cKL with regard to phosphatemetabolism are unclear.We tested the ability of cKL to regulate pathways and phenotypes associated with hyperphosphatemia in a mouse model ofCKD-mineral bone disorder andaKL-nullmice. Stable delivery of adeno-associated virus (AAV) expressing cKL to diabetic endothelial nitric oxide synthase-deficient mice or aKL-null mice reduced serum phosphate levels. Acute injection of recombinant cKL downregulated the renal sodium-phosphate cotransporter Npt2a in αKL-null mice supporting direct actions of cKL in the absence of mKL. αKL-null mice with sustained AAV-cKL expression had a 74%-78% reduction in aorta mineral content and a 72%-77% reduction in mineral volume compared with control-treated counterparts (P<0.01). Treatment of UMR-106 osteoblastic cells with cKL + FGF23 increased the phosphorylation of extracellular signal-regulated kinase 1/2 and induced Fgf23 expression. CRISPR/Cas9-mediateddeletion offibroblast growth factor receptor 1 (FGFR1) or pretreatment with inhibitors of mitogen-activated kinase kinase 1 or FGFR ablated these responses. In summary, sustained cKL treatment reduced hyperphosphatemia in a mouse model of CKD-mineral bone disorder, and it reduced hyperphosphatemia and prevented VC in mice without endogenous aKL. Furthermore, cKL stimulated Fgf23 in an FGFR1- dependentmanner in bone cells. Collectively, these findings indicate that cKL hasmKL-independent activity and suggest the potential for enhancing cKL activity in diseases of hyperphosphatemia with associated VC.

Original languageEnglish (US)
Pages (from-to)1162-1174
Number of pages13
JournalJournal of the American Society of Nephrology
Issue number4
StatePublished - Apr 2017

ASJC Scopus subject areas

  • Nephrology

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    Hum, J. M., O'Bryan, L. M., Tatiparthi, A. K., Cass, T. A., Clinkenbeard, E. L., Cramer, M. S., Bhaskaran, M., Johnson, R. L., Wilson, J. M., Smith, R. C., & White, K. E. (2017). Chronic hyperphosphatemia and vascular calcification are reduced by stable delivery of soluble klotho. Journal of the American Society of Nephrology, 28(4), 1162-1174.