Thursday, November 6, 2008

Renal Week 2008: Clotho

Makoto Kuro

Emerging role of Klotho

Klotho mouse has accelerated aging
due to insertion of gene missiong gene X by accident.
first model of human aging with multiple phenotypes.Question what is gene X
single pass transmembrain protein
it has some siaqlidase activity
gene expressed predominant\ly in the kidney and a little in the brain

does over expression of klotho surpress aging?
over expression extends mouse life by 30%
expressed in the distal convoluted tubules with weak expression in PT
the extracellular domain is clipped by ADAM 10 and then is a soluble factor

klotho -/- has similar phenotypes as FGF23 -/-

FGF is phophaturic hormone from the bones
gain of function causes hypophosphatemic rickets (vit D resistant)

FGF23 binds to FGF23 receptor plus Klotho

FGF23 requires klotho to activate FGF signaling
FGF lowers 1-alpha hydroxylase and increases 24-hydroxylase (deacticvate 1,25)
FGF?Klotho system surpresses PTH

agiing like phenotypes are caused by phosphate toxicity

soluble/secreted klotho independent of FGF23 increases renal phosphate wasting

sialidase activity activates TRPV5 which increases Ca current.

Link between |Klotho and CKD.

Mice lacking Klotho and ESRD share: casc calcification and hyperphosphatemia

mice with over expression of klotho are more resistant to vasc calcification and hyperphosphatemia in CKD model.
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