Retention of fetuin-A in renal tubular lumen protects the kidney from nephrocalcinosis in rats.
The serum glycoprotein fetuin-A is an important inhibitor of extraosseous calcification. The importance of fetuin-A has been confirmed in fetuin-A null mice, which develop widespread extraosseous calcification including the kidney. However, the mechanism how fetuin-A protects kidneys from nephrocalcinosis remains uncertain. Here, we demonstrate that intratubular fetuin-A plays a role in the prevention of nephrocalcinosis in the proximal tubules. Although normal rat kidney did not express mRNA for fetuin-A, we found punctate immunohistochemical staining of fetuin-A mainly in the S1 segment of the proximal tubules. The staining pattern suggested that fetuin-A passed through the slit diaphragm, traveled in the proximal tubular lumen, and was introduced into proximal tubular cells by megalin-mediated endocytosis. To test this hypothesis, we inhibited the function of megalin by intravenous injection of histidine-tagged soluble receptor-associated protein (His-sRAP), a megalin inhibitor. His-sRAP injection diminished fetuin-A staining in the proximal tubules and led to urinary excretion of fetuin-A. We further analyzed the role of fetuin-A in nephrocalcinosis. Continuous injection of parathyroid hormone (PTH) 1-34 induced nephrocalcinosis mainly in the proximal tubules in rats. His-sRAP retained fetuin-A in renal tubular lumen and thereby protected the kidneys of PTH-treated rats from calcification. Our findings suggest that tubular luminal fetuin-A works as a natural inhibitor against calcification in the proximal tubules under PTH-loaded condition.
Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan.
Isao
I
Matsui
Takayuki
T
Hamano
Satoshi
S
Mikami
Kazunori
K
Inoue
Akihiro
A
Shimomura
Yasuyuki
Y
Nagasawa
Toshimi
T
Michigami
Tomokazu
T
Ohnishi
Naohiko
N
Fujii
Chikako
C
Nakano
Yasuo
Y
Kusunoki
Harumi
H
Kitamura
Hirotsugu
H
Iwatani
Yoshitsugu
Y
Takabatake
Jun-ya
JY
Kaimori
Go
G
Matsuba
Kento
K
Okoshi
Hiromi
H
Kimura-Suda
Yoshiharu
Y
Tsubakihara
Hiromi
H
Rakugi
Yoshitaka
Y
Isaka
D000818:Animals; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009397:Nephrocalcinosis / Q000378:metabolism* / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D060749:alpha-2-HS-Glycoprotein / Q000378:metabolism*
D026561:Low Density Lipoprotein Receptor-Related Protein-2; D060749:alpha-2-HS-Glycoprotein