INVESTIGADORES
CORTÉS MarÍa alicia
congresos y reuniones científicas
Título:
HYPERPHOSPHATEMIA INDUCES INTEGRIN LINKED KINASE EXPRESSION AND LEADS TO CELLULAR SENESCENCE AND AGING: STUDIES IN VIVO AND IN VITRO
Autor/es:
NURIA TROYANO; MARÍA DEL NOGAL; INÉS MORA; GEMMA OLMOS; M. LUISA DIEZ-MARQUEZ; M. ALICIA CORTÉS; SUSANA LOPEZ-ONGIL; PALOMA MARTÍN; DIEGO RODRIGUEZ-PUYOL; MARIA P. RUIZ-TORRES
Lugar:
Istanbul
Reunión:
Simposio; 50th ERA-EDTA CONGRESS; 2013
Institución organizadora:
EDTA
Resumen:
Introduction and Aims: Hyperphosphatemia
has been related to premature aging in the Klotho deficient mice and in
de FGF23 KO mice. Serum phosphate
levels inversely correlated with species
lifespan. Senescence is a cell cycle arrest promoted by the replicative
life of the
cells or by stressful stimuli. Mechanisms
involved in aging-induced by hyperphosphatemia are actually unknown.
Integrin linked
kinase (ILK) is a protein involved in the
relationship between cells and surrounding extracellular matrix
regulating cellular
proliferation and survival. It has been
previously described that ILK was increased in old animals. Aim: To
explore the role
of hyperphosphatemia in renal and vascular
aging. We propose that serum phosphate levels increases with aging in
mice and
promote the upregulation of the ILK expression
leading to cellular senescence.
Methods: We compare 3
months old C57Bl 6 mice with 15 months old mice. We analyze serum
phosphate by a colorimetric method and the
mRNA expression of Klotho, NaPi2a transporter,
1a-hydroxylase and 24-hydroxylase and ILK by real time RT- PCR in
kidney. We
analyzed the expression of senescent genes, p53
and p16 by western blot in kidney from these animals . To analyze
whether
hyperphosphatemia induces ILK expression leading
to cellular senescence we used human vascular smooth muscle cells
(HVSMC)
treated with 10 mM beta-glycerophosphate (BGP)
during 24, 48 or 72 hours.
Results: We found that
15 month old mice show higher serum phosphate, decreased Klotho
expression, increased NaPi2a and 1α-hydroxylase
expressions and decreased 24-hydroxylase
expression than young animals. Old animals also have a higher expression
of ILK.
A significant correlation was found between high
serum phosphate and increased ILK expression. We found an increase in
the
expression of senescent genes p53 and p16 in old
animals. We found that BGP increases ILK, p53 and p16 expression,
assessed
by western blot, and induces senescence
associated- beta-galactosidase expression evaluated by confocal
microscopy with a
fluorescent probe. The increase was inhibited
using the inhibitor of Pit-1, phosphonoformic acid (PFA) 0.5mM. ILK
silenced
with small siRNA in HVSMC inhibited the
senescence induced by BGP.
Conclusions: We
conclude that old animals show a decreased expression of Klotho protein
disturbing the phosphate homeostasis and leading
to the increase in serum phosphate levels. The
resulting hyperphosphatemia seem to induce senescence in kidney and
vascular
cells through the increment of ILK expression.