Klotho : clinical aspects

KLOTHO: CLINICAL ASPECTS
KLOTHO: CLINICAL ASPECTS
Pr Dominique Prié,
Université Paris Descartes, Faculté de Médecine,
Institut Necker
-
Enfants Malades INSERM
Institut Necker
-
Enfants Malades INSERM
Service des Explorations Fonctionnelles
Hôpital Necker-Enfants Malades, Paris, France

THE DIFFERENT FORMS OF KLOTHO
FGF
-
23
Circulating Klotho
1014 amino acids, short transmembrane and cytoplasmic segment
FGF-23
FGFR
FGF
-
23
membrane form
of Klotho
FRS2α
Shedding
(ADAMs 10, 17?)
KL1
KL2
PLC
γ
FGFR
(ADAMs 10, 17?)
KL1?
Alternative splicing
ERK
AKT
PLC
γ
PKC
IP3
βcatenine

HOW KLOTHO COULD MODIFY CLINICAL PRACTICE?
1- Is Klotho important for the diagnosis?
2- Can Klotho be a biomarker?
Can Klotho predict a risk? does this lead to a change of caring or treatment?
•Variants in Klotho gene
•mRNA expression in specific tissues
•Protein expression in specific tissues
•Protein level in blood
3- Is Klotho a surrogate or an independent biomarker?
4- Can Klotho be a therapeutic target?
•Can over or down expression of Klotho improve the prognosis of a disorder or
lower adverse outcomes?
•How can we modify Klotho expression?

Kuro-o, Nature
1997, 390:45
EXPRESSION OF KLOTHO
KIDNEY: proximal + distal tubule Parathyroid gland
1997, 390:45
Ben-Dov, JCI 2007;
117, 12: 4003
Hu Faseb J 2010
The tissue-specific expression of Klotho is controlled by the methylation of Klotho promoter
(Azuma FASEB J. 2012)

IS KLOTHO EXPRESSED IN THE ARTERY WALL?
Healthy human MICE
(Lim Circulation. 2012;125:2243-2255)
Lindberg (2013). PLoS ONE 8: e60658.
Specific disruption of Klotho gene
in smooth muscle cell of artery
wall: No phenotype
Specificity of the antibody?