Sustained Klotho delivery reduces serum phosphate in a model of diabetic nephropathy

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

Research output: Contribution to journalArticle

Abstract

Diabetic nephropathy (DN) is a primary cause of end-stage renal disease and is becoming more prevalent because of the global rise in type 2 diabetes. A model of DN, the db/db uninephrectomized ( db/db-uni) mouse, is characterized by obesity, as well as compromised renal function. This model also manifests defects in mineral metabolism common in DN, including hyperphosphatemia, which leads to severe endocrine disease. The FGF23 coreceptor, α-Klotho, circulates as a soluble, cleaved form (cKL) and may directly influence phosphate handling. Our study sought to test the effects of cKL on mineral metabolism in db/db-uni mice. Mice were placed into either mild or moderate disease groups on the basis of the albumin-to-creatinine ratio (ACR). Body weights of db/db-uni mice were significantly greater across the study compared with lean controls regardless of disease severity. Adeno-associated cKL administration was associated with increased serum Klotho, intact, bioactive FGF23 (iFGF23), and COOH-terminal fragments of FGF23 ( P < 0.05). Blood urea nitrogen was improved after cKL administration, and cKL corrected hyperphosphatemia in the high- and low-ACR db/db-uni groups. Interestingly, 2 wk after cKL delivery, blood glucose levels were significantly reduced in db/db-uni mice with high ACR ( P < 0.05). Interestingly, several genes associated with stabilizing active iFGF23 were also increased in the osteoblastic UMR-106 cell line with cKL treatment. In summary, delivery of cKL to a model of DN normalized blood phosphate levels regardless of disease severity, supporting the concept that targeting cKL-affected pathways could provide future therapeutic avenues in DN. NEW & NOTEWORTHY In this work, systemic and continuous delivery of the "soluble" or "cleaved" form of the FGF23 coreceptor α-Klotho (cKL) via adeno-associated virus to a rodent model of diabetic nephropathy (DN), the db/db uninephrectomized mouse, normalized blood phosphate levels regardless of disease severity. This work supports the concept that targeting cKL-affected pathways could provide future therapeutic avenues for the severe mineral metabolism defects associated with DN.

Original languageEnglish (US)
Pages (from-to)854-862
Number of pages9
JournalJournal of applied physiology (Bethesda, Md. : 1985)
Volume126
Issue number4
DOIs
StatePublished - Apr 1 2019

Fingerprint

Diabetic Nephropathies
Phosphates
Serum
Hyperphosphatemia
Minerals
Albumins
Creatinine
Endocrine System Diseases
Dependovirus
Blood Urea Nitrogen
Type 2 Diabetes Mellitus
Chronic Kidney Failure
Blood Glucose
Rodentia
Obesity
Body Weight
Kidney
Cell Line
Therapeutics
Genes

Keywords

  • cKL
  • diabetes
  • FGF23
  • Klotho
  • phosphate

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Sustained Klotho delivery reduces serum phosphate in a model of diabetic nephropathy. / Hum, Julia M.; O'Bryan, Linda M.; Tatiparthi, Arun K.; Clinkenbeard, Erica L.; Ni, Pu; Cramer, Martin S.; Bhaskaran, Manoj; Johnson, Robert L.; Wilson, Jonathan M.; Smith, Rosamund C.; White, Kenneth.

In: Journal of applied physiology (Bethesda, Md. : 1985), Vol. 126, No. 4, 01.04.2019, p. 854-862.

Research output: Contribution to journalArticle

Hum, JM, O'Bryan, LM, Tatiparthi, AK, Clinkenbeard, EL, Ni, P, Cramer, MS, Bhaskaran, M, Johnson, RL, Wilson, JM, Smith, RC & White, K 2019, 'Sustained Klotho delivery reduces serum phosphate in a model of diabetic nephropathy', Journal of applied physiology (Bethesda, Md. : 1985), vol. 126, no. 4, pp. 854-862. https://doi.org/10.1152/japplphysiol.00838.2018
Hum, Julia M. ; O'Bryan, Linda M. ; Tatiparthi, Arun K. ; Clinkenbeard, Erica L. ; Ni, Pu ; Cramer, Martin S. ; Bhaskaran, Manoj ; Johnson, Robert L. ; Wilson, Jonathan M. ; Smith, Rosamund C. ; White, Kenneth. / Sustained Klotho delivery reduces serum phosphate in a model of diabetic nephropathy. In: Journal of applied physiology (Bethesda, Md. : 1985). 2019 ; Vol. 126, No. 4. pp. 854-862.
@article{260a34e9a992415bac5bbe50b515d1c7,
title = "Sustained Klotho delivery reduces serum phosphate in a model of diabetic nephropathy",
abstract = "Diabetic nephropathy (DN) is a primary cause of end-stage renal disease and is becoming more prevalent because of the global rise in type 2 diabetes. A model of DN, the db/db uninephrectomized ( db/db-uni) mouse, is characterized by obesity, as well as compromised renal function. This model also manifests defects in mineral metabolism common in DN, including hyperphosphatemia, which leads to severe endocrine disease. The FGF23 coreceptor, α-Klotho, circulates as a soluble, cleaved form (cKL) and may directly influence phosphate handling. Our study sought to test the effects of cKL on mineral metabolism in db/db-uni mice. Mice were placed into either mild or moderate disease groups on the basis of the albumin-to-creatinine ratio (ACR). Body weights of db/db-uni mice were significantly greater across the study compared with lean controls regardless of disease severity. Adeno-associated cKL administration was associated with increased serum Klotho, intact, bioactive FGF23 (iFGF23), and COOH-terminal fragments of FGF23 ( P < 0.05). Blood urea nitrogen was improved after cKL administration, and cKL corrected hyperphosphatemia in the high- and low-ACR db/db-uni groups. Interestingly, 2 wk after cKL delivery, blood glucose levels were significantly reduced in db/db-uni mice with high ACR ( P < 0.05). Interestingly, several genes associated with stabilizing active iFGF23 were also increased in the osteoblastic UMR-106 cell line with cKL treatment. In summary, delivery of cKL to a model of DN normalized blood phosphate levels regardless of disease severity, supporting the concept that targeting cKL-affected pathways could provide future therapeutic avenues in DN. NEW & NOTEWORTHY In this work, systemic and continuous delivery of the {"}soluble{"} or {"}cleaved{"} form of the FGF23 coreceptor α-Klotho (cKL) via adeno-associated virus to a rodent model of diabetic nephropathy (DN), the db/db uninephrectomized mouse, normalized blood phosphate levels regardless of disease severity. This work supports the concept that targeting cKL-affected pathways could provide future therapeutic avenues for the severe mineral metabolism defects associated with DN.",
keywords = "cKL, diabetes, FGF23, Klotho, phosphate",
author = "Hum, {Julia M.} and O'Bryan, {Linda M.} and Tatiparthi, {Arun K.} and Clinkenbeard, {Erica L.} and Pu Ni and Cramer, {Martin S.} and Manoj Bhaskaran and Johnson, {Robert L.} and Wilson, {Jonathan M.} and Smith, {Rosamund C.} and Kenneth White",
year = "2019",
month = "4",
day = "1",
doi = "10.1152/japplphysiol.00838.2018",
language = "English (US)",
volume = "126",
pages = "854--862",
journal = "Journal of Applied Physiology",
issn = "8750-7587",
publisher = "American Physiological Society",
number = "4",

}

TY - JOUR

T1 - Sustained Klotho delivery reduces serum phosphate in a model of diabetic nephropathy

AU - Hum, Julia M.

AU - O'Bryan, Linda M.

AU - Tatiparthi, Arun K.

AU - Clinkenbeard, Erica L.

AU - Ni, Pu

AU - Cramer, Martin S.

AU - Bhaskaran, Manoj

AU - Johnson, Robert L.

AU - Wilson, Jonathan M.

AU - Smith, Rosamund C.

AU - White, Kenneth

PY - 2019/4/1

Y1 - 2019/4/1

N2 - Diabetic nephropathy (DN) is a primary cause of end-stage renal disease and is becoming more prevalent because of the global rise in type 2 diabetes. A model of DN, the db/db uninephrectomized ( db/db-uni) mouse, is characterized by obesity, as well as compromised renal function. This model also manifests defects in mineral metabolism common in DN, including hyperphosphatemia, which leads to severe endocrine disease. The FGF23 coreceptor, α-Klotho, circulates as a soluble, cleaved form (cKL) and may directly influence phosphate handling. Our study sought to test the effects of cKL on mineral metabolism in db/db-uni mice. Mice were placed into either mild or moderate disease groups on the basis of the albumin-to-creatinine ratio (ACR). Body weights of db/db-uni mice were significantly greater across the study compared with lean controls regardless of disease severity. Adeno-associated cKL administration was associated with increased serum Klotho, intact, bioactive FGF23 (iFGF23), and COOH-terminal fragments of FGF23 ( P < 0.05). Blood urea nitrogen was improved after cKL administration, and cKL corrected hyperphosphatemia in the high- and low-ACR db/db-uni groups. Interestingly, 2 wk after cKL delivery, blood glucose levels were significantly reduced in db/db-uni mice with high ACR ( P < 0.05). Interestingly, several genes associated with stabilizing active iFGF23 were also increased in the osteoblastic UMR-106 cell line with cKL treatment. In summary, delivery of cKL to a model of DN normalized blood phosphate levels regardless of disease severity, supporting the concept that targeting cKL-affected pathways could provide future therapeutic avenues in DN. NEW & NOTEWORTHY In this work, systemic and continuous delivery of the "soluble" or "cleaved" form of the FGF23 coreceptor α-Klotho (cKL) via adeno-associated virus to a rodent model of diabetic nephropathy (DN), the db/db uninephrectomized mouse, normalized blood phosphate levels regardless of disease severity. This work supports the concept that targeting cKL-affected pathways could provide future therapeutic avenues for the severe mineral metabolism defects associated with DN.

AB - Diabetic nephropathy (DN) is a primary cause of end-stage renal disease and is becoming more prevalent because of the global rise in type 2 diabetes. A model of DN, the db/db uninephrectomized ( db/db-uni) mouse, is characterized by obesity, as well as compromised renal function. This model also manifests defects in mineral metabolism common in DN, including hyperphosphatemia, which leads to severe endocrine disease. The FGF23 coreceptor, α-Klotho, circulates as a soluble, cleaved form (cKL) and may directly influence phosphate handling. Our study sought to test the effects of cKL on mineral metabolism in db/db-uni mice. Mice were placed into either mild or moderate disease groups on the basis of the albumin-to-creatinine ratio (ACR). Body weights of db/db-uni mice were significantly greater across the study compared with lean controls regardless of disease severity. Adeno-associated cKL administration was associated with increased serum Klotho, intact, bioactive FGF23 (iFGF23), and COOH-terminal fragments of FGF23 ( P < 0.05). Blood urea nitrogen was improved after cKL administration, and cKL corrected hyperphosphatemia in the high- and low-ACR db/db-uni groups. Interestingly, 2 wk after cKL delivery, blood glucose levels were significantly reduced in db/db-uni mice with high ACR ( P < 0.05). Interestingly, several genes associated with stabilizing active iFGF23 were also increased in the osteoblastic UMR-106 cell line with cKL treatment. In summary, delivery of cKL to a model of DN normalized blood phosphate levels regardless of disease severity, supporting the concept that targeting cKL-affected pathways could provide future therapeutic avenues in DN. NEW & NOTEWORTHY In this work, systemic and continuous delivery of the "soluble" or "cleaved" form of the FGF23 coreceptor α-Klotho (cKL) via adeno-associated virus to a rodent model of diabetic nephropathy (DN), the db/db uninephrectomized mouse, normalized blood phosphate levels regardless of disease severity. This work supports the concept that targeting cKL-affected pathways could provide future therapeutic avenues for the severe mineral metabolism defects associated with DN.

KW - cKL

KW - diabetes

KW - FGF23

KW - Klotho

KW - phosphate

UR - http://www.scopus.com/inward/record.url?scp=85064213280&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85064213280&partnerID=8YFLogxK

U2 - 10.1152/japplphysiol.00838.2018

DO - 10.1152/japplphysiol.00838.2018

M3 - Article

C2 - 30605400

AN - SCOPUS:85064213280

VL - 126

SP - 854

EP - 862

JO - Journal of Applied Physiology

JF - Journal of Applied Physiology

SN - 8750-7587

IS - 4

ER -