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 White

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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 of mKL. The functions of cKL with regard to phosphate metabolism are unclear. We tested the ability of cKL to regulate pathways and phenotypes associated with hyperphosphatemia in a mouse model of CKD-mineral bone disorder and αKL-null mice. Stable delivery of adeno-associated virus (AAV) expressing cKL to diabetic endothelial nitric oxide synthase-deficient mice or αKL-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-mediated deletion of fibroblast 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 αKL. Furthermore, cKL stimulated Fgf23 in an FGFR1-dependent manner in bone cells. Collectively, these findings indicate that cKL has mKL-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 : JASN
Volume28
Issue number4
DOIs
StatePublished - Apr 1 2017

Fingerprint

Hyperphosphatemia
Vascular Calcification
Minerals
Receptor, Fibroblast Growth Factor, Type 1
Dependovirus
Bone and Bones
Sodium-Phosphate Cotransporter Proteins
Phosphotransferases
Clustered Regularly Interspaced Short Palindromic Repeats
Phosphates
Mitogen-Activated Protein Kinase 3
Nitric Oxide Synthase Type III
Mitogen-Activated Protein Kinase 1
Mitogens
Aorta
Membrane Proteins
Down-Regulation
Phosphorylation
Phenotype
Kidney

Keywords

  • alpha-klotho
  • bone
  • db/db-eNOS
  • FGF23
  • hyperphosphatemia
  • osteocyte

ASJC Scopus subject areas

  • Nephrology

Cite this

Chronic Hyperphosphatemia and Vascular Calcification Are Reduced by Stable Delivery of Soluble Klotho. / Hum, Julia M.; O'Bryan, Linda M.; Tatiparthi, Arun K.; Cass, Taryn A.; Clinkenbeard, Erica L.; Cramer, Martin S.; Bhaskaran, Manoj; Johnson, Robert L.; Wilson, Jonathan M.; Smith, Rosamund C.; White, Kenneth.

In: Journal of the American Society of Nephrology : JASN, Vol. 28, No. 4, 01.04.2017, p. 1162-1174.

Research output: Contribution to journalArticle

Hum, JM, O'Bryan, LM, Tatiparthi, AK, Cass, TA, Clinkenbeard, EL, Cramer, MS, Bhaskaran, M, Johnson, RL, Wilson, JM, Smith, RC & White, K 2017, 'Chronic Hyperphosphatemia and Vascular Calcification Are Reduced by Stable Delivery of Soluble Klotho', Journal of the American Society of Nephrology : JASN, vol. 28, no. 4, pp. 1162-1174. https://doi.org/10.1681/ASN.2015111266
Hum, Julia M. ; O'Bryan, Linda M. ; Tatiparthi, Arun K. ; Cass, Taryn A. ; Clinkenbeard, Erica L. ; Cramer, Martin S. ; Bhaskaran, Manoj ; Johnson, Robert L. ; Wilson, Jonathan M. ; Smith, Rosamund C. ; White, Kenneth. / Chronic Hyperphosphatemia and Vascular Calcification Are Reduced by Stable Delivery of Soluble Klotho. In: Journal of the American Society of Nephrology : JASN. 2017 ; Vol. 28, No. 4. pp. 1162-1174.
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abstract = "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 of mKL. The functions of cKL with regard to phosphate metabolism are unclear. We tested the ability of cKL to regulate pathways and phenotypes associated with hyperphosphatemia in a mouse model of CKD-mineral bone disorder and αKL-null mice. Stable delivery of adeno-associated virus (AAV) expressing cKL to diabetic endothelial nitric oxide synthase-deficient mice or αKL-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-mediated deletion of fibroblast 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 αKL. Furthermore, cKL stimulated Fgf23 in an FGFR1-dependent manner in bone cells. Collectively, these findings indicate that cKL has mKL-independent activity and suggest the potential for enhancing cKL activity in diseases of hyperphosphatemia with associated VC.",
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