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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2013 |
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| Erschienen: |
2013 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:304 |
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| Enthalten in: |
American journal of physiology. Renal physiology - 304(2013), 6 vom: 15. März, Seite F751-60 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Matsui, Isao [VerfasserIn] |
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| Links: |
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| Themen: |
Alpha-2-HS-Glycoprotein |
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| Anmerkungen: |
Date Completed 16.05.2013 Date Revised 18.03.2013 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1152/ajprenal.00329.2012 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM224410636 |
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| 100 | 1 | |a Matsui, Isao |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Retention of fetuin-A in renal tubular lumen protects the kidney from nephrocalcinosis in rats |
| 264 | 1 | |c 2013 | |
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| 500 | |a Date Revised 18.03.2013 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Low Density Lipoprotein Receptor-Related Protein-2 |2 NLM | |
| 650 | 7 | |a alpha-2-HS-Glycoprotein |2 NLM | |
| 700 | 1 | |a Hamano, Takayuki |e verfasserin |4 aut | |
| 700 | 1 | |a Mikami, Satoshi |e verfasserin |4 aut | |
| 700 | 1 | |a Inoue, Kazunori |e verfasserin |4 aut | |
| 700 | 1 | |a Shimomura, Akihiro |e verfasserin |4 aut | |
| 700 | 1 | |a Nagasawa, Yasuyuki |e verfasserin |4 aut | |
| 700 | 1 | |a Michigami, Toshimi |e verfasserin |4 aut | |
| 700 | 1 | |a Ohnishi, Tomokazu |e verfasserin |4 aut | |
| 700 | 1 | |a Fujii, Naohiko |e verfasserin |4 aut | |
| 700 | 1 | |a Nakano, Chikako |e verfasserin |4 aut | |
| 700 | 1 | |a Kusunoki, Yasuo |e verfasserin |4 aut | |
| 700 | 1 | |a Kitamura, Harumi |e verfasserin |4 aut | |
| 700 | 1 | |a Iwatani, Hirotsugu |e verfasserin |4 aut | |
| 700 | 1 | |a Takabatake, Yoshitsugu |e verfasserin |4 aut | |
| 700 | 1 | |a Kaimori, Jun-ya |e verfasserin |4 aut | |
| 700 | 1 | |a Matsuba, Go |e verfasserin |4 aut | |
| 700 | 1 | |a Okoshi, Kento |e verfasserin |4 aut | |
| 700 | 1 | |a Kimura-Suda, Hiromi |e verfasserin |4 aut | |
| 700 | 1 | |a Tsubakihara, Yoshiharu |e verfasserin |4 aut | |
| 700 | 1 | |a Rakugi, Hiromi |e verfasserin |4 aut | |
| 700 | 1 | |a Isaka, Yoshitaka |e verfasserin |4 aut | |
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