1. Retention of fetuin-A in renal tubular lumen protects the kidney from nephrocalcinosis in rats
- Author
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Hiromi Rakugi, Kazunori Inoue, Hirotsugu Iwatani, Yoshitsugu Takabatake, Yasuo Kusunoki, Yasuyuki Nagasawa, Tomokazu Ohnishi, Isao Matsui, Satoshi Mikami, Hiromi Kimura-Suda, Yoshitaka Isaka, Go Matsuba, Naohiko Fujii, Akihiro Shimomura, Toshimi Michigami, Takayuki Hamano, Yoshiharu Tsubakihara, Chikako Nakano, Kento Okoshi, Jun-ya Kaimori, and Harumi Kitamura
- Subjects
Male ,Null mice ,medicine.medical_specialty ,alpha-2-HS-Glycoprotein ,Physiology ,Lumen (anatomy) ,Biology ,Kidney Tubules, Proximal ,Mice ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,chemistry.chemical_classification ,Kidney ,Extraosseous Calcification ,medicine.disease ,Fetuin ,Rats ,Mice, Inbred C57BL ,Low Density Lipoprotein Receptor-Related Protein-2 ,Nephrocalcinosis ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Lysosomes ,Glycoprotein - Abstract
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.
- Published
- 2013