Klotho protein activates the PKC pathway in the kidney and testis and suppresses 25-hydroxyvitamin D3 1alpha-hydroxylase gene expression.
Homozygous Klotho mutant (kl-/-) mice exhibit a variety of phenotypes resembling human aging, including arteriosclerosis, infertility, skin atrophy, osteoporosis, and short life span. Calcium abnormality, one of the phenotypes in kl-/- mice, is thought to be due to the elevated gene expression of 25-hydroxyvitamin D3 1alpha-hydroxylase in the kidney. We studied 25-hydroxy-vitamin D3 1alpha-hydroxylase gene expression using a Klotho plasmid that we had previously constructed for Klotho protein production. It was found that Klotho protein medium upregulated cAMP and the PKC pathway, and suppressed 25-hydroxyvitamin D3 1alpha-hydrox-ylase in kidney cells. However, both cAMP and PKC are known to elevate 25-hydroxyvitamin D3 1alpha-hydroxylase gene expression, therefore, another unknown calcium regulation pathway using Klotho protein medium might exist. Furthermore, we found that activation of the PKC pathway by Klotho was observed only in the kidney and testis, where the Klotho gene is expressed, although activation of the cAMP pathway was observed in any kind of cell. These data suggest that calcium regulation through 25-hydroxyvitamin D3 1alpha-hydroxylase by Klotho depends on non-cAMP and a non-PKC pathway and that the Klotho protein may have different signaling pathways, depending on the Klotho gene expression in different cells and organs.
Imai
Michio
M
Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
Ishikawa
Kazuhiko
K
Matsukawa
Naomichi
N
Kida
Iwao
I
Ohta
Junsuke
J
Ikushima
Masashi
M
Chihara
Yukana
Y
Rui
Xu
X
Rakugi
Hiromi
H
Ogihara
Toshio
T
D000818:Animals; D002460:Cell Line; D017077:Culture Media, Conditioned / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D005966:Glucuronidase; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000201:enzymology*; D000090265:Klotho Proteins; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D011493:Protein Kinase C / Q000378:metabolism*; D012313:RNA / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology; D013250:Steroid Hydroxylases / Q000235:genetics* / Q000378:metabolism; D013737:Testis / Q000166:cytology / Q000201:enzymology*; D065668:Vitamin D3 24-Hydroxylase
D017077:Culture Media, Conditioned; D008565:Membrane Proteins; D012313:RNA; D003577:Cytochrome P-450 Enzyme System; D000242:Cyclic AMP; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D011493:Protein Kinase C; D005966:Glucuronidase; D000090265:Klotho Proteins