Download Dear President - Era-Edta

CALL FOR EUROPEAN RESEARCH CENTERS
INTERESTED IN RECEIVING A FELLOW
FROM ANOTHER EUROPEAN COUNTRY
Name of the Institution: Department of Health Sciences, University of
Milan____
Web site of the Institution: www.unimi.it ______________________
Contact person: Professor Mario Cozzolino _________________
Address: Laboratory of Experimental Nephrology, San Paolo
Hospital,via di Rudini, 8
Postal code: 20142______ City: Milan ______________
Country: Italy ________________________________
Phone: +39(0)281844381 _____ Fax: +39(0)281844475_________
E-mail: [email protected] _________________
Synopsis on research programme in Nephrology/ Dialysis/ Transplantation
(the synopsis must not exceed 3500 character –font 12, word format only-).
Cardiovascular diseases are a worldwide leading cause of morbidity and
mortality. Patients with chronic kidney disease (CKD) have an increased risk of
cardiovascular morbidity/mortality that in dialysis patients may be 100-fold higher
than in general population. Arterial calcification (AC) is an independent predictor
of cardiovascular morbidity/mortality. It is very frequent in CKD patients where it
is a sign of calcified arteriopathy causing arterial stiffness and frailty. AC
develops in the tunica media and intima of the arteries, but subcontinuous medial
deposits are typical of CKD.
The alterations of calcium-phosphate metabolism in CKD are a cause of arterial
calcium-phosphate deposition that resembles osteoblast-mediated bone
formation, as proposed by Virchow in nineteenth century. Hyperphosphatemia
and hyperparathyroidism have a crucial role in calcification process because they
activate vascular smooth muscle cells to adopt an osteoblast phenotype that
allows them to produce alkaline phosphatase, osterix, Runx2, Msx2, bone
morphogenetic proteins (BMP), type 1collagen, osteopontin and other proteins
implicated in osteogenesis. All these substances have been found in the wall of
calcified vessels from CKD patients with different analytic methods.
Hyperphosphatemia stimulates vascular smooth muscle cells differentiation into
osteoblast-like cells because a specific phosphate carrier (NPT3) drives cell
phosphate overload that stimulates the transcription of bone formation proteins.
Thus, these cells acquire the capability to produce type 1 collagen and bone
matrix vesicles and can deposit apatite on collagen fibers. This occurs in artery
media tunica where it results in arterial stiffness that increases arterial blood
pressure and decreases blood flux rate in coronary district, thus, causing cardiac
hypertrophy and dilatative cardiomyopathy.
Our hypothesis is that arterial calcification and cardiovascular risk have a genetic
predisposition in CKD patients and that calcium-sensing receptor (CASR)
downregulation significantly contributes to the predisposition to the artery
calcification.
Therefore the general aim of this study is to identify genetic, biochemical and
functional markers of arterial damage useful to recognize patients with chronic
kidney disease (CKD) at risk of cardiovascular events.
Cellular studies will be performed in cultured vascular smooth muscle cells, to
study change of gene expression during their differentiation into osteoblast-like
cells. Also, we will investigate intracellular signals associated with mineral
deposition and to study the effect of calcimimetics in delaying the progression of
smooth muscle cells calcification in vitro.
In fact, AC is anticipated by the differentiation of vascular smooth muscle cells
into osteoblast-like cells able to express proteins typical of bone formation. The
findings of these experiments will be used to define potential antagonists of the
osteoblastic differentiation that may also inhibit AC formation.
Our preliminary published data showed that ascorbic acid combined with
inorganic phosphate increases calcium deposition in rat vascular smooth muscle
cells. At the same time, the combined effect of ascorbic acid and phosphate
resulted in phenotype changes in vascular smooth muscle cells and enhanced
bone mineralization key gene expression. These in vitro preliminary data suggest
the potential role of ascorbic acid combined to phosphate in worsening AC (Ciceri
P, Volpi E, Brenna I et al. Combined effects of acsorbic acid and phosphatte
onrat VSMC osteoblastic differentiation. Nephrol Dial Transplant 2012).
The mechanism of calcium-phosphate deposition will be evaluated in cultured
human vascular smooth muscle cells by high phosphate to change phenotype in
osteoblastic-like cells.
Current lines of research.
Pathogenesis of vascular calcification
Treatment of vascular calcification
Treatment of hyperphosphatemia
Prevention of secondary hyperparathyroridism
Research/es in which the Fellow will be involved.
Pathogenesis of vascular calcification
Treatment of vascular calcification
Treatment of hyperphosphatemia
Prevention of secondary hyperparathyroridism
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