TY - JOUR
T1 - High Fibroblast Growth Factor 23 concentrations in experimental renal failure impair calcium handling in cardiomyocytes
AU - the NIGRAM consortium
AU - Verkaik, Melissa
AU - Oranje, Maarten
AU - Abdurrachim, Desiree
AU - Goebel, Max
AU - Gam, Zeineb
AU - Prompers, Jeanine J.
AU - Helmes, Michiel
AU - ter Wee, Pieter M.
AU - van der Velden, Jolanda
AU - Kuster, Diederik W.
AU - Vervloet, Marc G.
AU - Eringa, Etto C.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - The overwhelming majority of patients with chronic kidney disease (CKD) die prematurely before reaching end-stage renal disease, mainly due to cardiovascular causes, of which heart failure is the predominant clinical presentation. We hypothesized that CKD-induced increases of plasma FGF23 impair cardiac diastolic and systolic function. To test this, mice were subjected to 5/6 nephrectomy (5/6Nx) or were injected with FGF23 for seven consecutive days. Six weeks after surgery, plasma FGF23 was higher in 5/6Nx mice compared to sham mice (720 ± 31 vs. 256 ± 3 pg/mL, respectively, P = 0.034). In cardiomyocytes isolated from both 5/6Nx and FGF23 injected animals the rise of cytosolic calcium during systole was slowed (−13% and −19%, respectively) as was the decay of cytosolic calcium during diastole (−15% and −21%, respectively) compared to controls. Furthermore, both groups had similarly decreased peak cytosolic calcium content during systole. Despite lower cytosolic calcium contents in CKD or FGF23 pretreated animals, no changes were observed in contractile parameters of cardiomyocytes between the groups. Expression of calcium handling proteins and cardiac troponin I phosphorylation were similar between groups. Blood pressure, the heart weight:tibia length ratio, α-MHC/β-MHC ratio and ANF mRNA expression, and systolic and diastolic function as measured by MRI did not differ between groups. In conclusion, the rapid, CKD-induced rise in plasma FGF23 and the similar decrease in cardiomyocyte calcium transients in modeled kidney disease and following 1-week treatment with FGF23 indicate that FGF23 partly mediates cardiomyocyte dysfunction in CKD.
AB - The overwhelming majority of patients with chronic kidney disease (CKD) die prematurely before reaching end-stage renal disease, mainly due to cardiovascular causes, of which heart failure is the predominant clinical presentation. We hypothesized that CKD-induced increases of plasma FGF23 impair cardiac diastolic and systolic function. To test this, mice were subjected to 5/6 nephrectomy (5/6Nx) or were injected with FGF23 for seven consecutive days. Six weeks after surgery, plasma FGF23 was higher in 5/6Nx mice compared to sham mice (720 ± 31 vs. 256 ± 3 pg/mL, respectively, P = 0.034). In cardiomyocytes isolated from both 5/6Nx and FGF23 injected animals the rise of cytosolic calcium during systole was slowed (−13% and −19%, respectively) as was the decay of cytosolic calcium during diastole (−15% and −21%, respectively) compared to controls. Furthermore, both groups had similarly decreased peak cytosolic calcium content during systole. Despite lower cytosolic calcium contents in CKD or FGF23 pretreated animals, no changes were observed in contractile parameters of cardiomyocytes between the groups. Expression of calcium handling proteins and cardiac troponin I phosphorylation were similar between groups. Blood pressure, the heart weight:tibia length ratio, α-MHC/β-MHC ratio and ANF mRNA expression, and systolic and diastolic function as measured by MRI did not differ between groups. In conclusion, the rapid, CKD-induced rise in plasma FGF23 and the similar decrease in cardiomyocyte calcium transients in modeled kidney disease and following 1-week treatment with FGF23 indicate that FGF23 partly mediates cardiomyocyte dysfunction in CKD.
KW - Calcium
KW - FGF23
KW - cardiac
KW - chronic kidney disease
KW - mineral bone disease
UR - http://www.scopus.com/inward/record.url?scp=85045527622&partnerID=8YFLogxK
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85045527622&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/29611320
U2 - https://doi.org/10.14814/phy2.13591
DO - https://doi.org/10.14814/phy2.13591
M3 - Article
C2 - 29611320
SN - 2051-817X
VL - 6
JO - Physiological reports
JF - Physiological reports
IS - 7
M1 - e13591
ER -