Megalin-mediated endocytosis of cystatin C in proximal tubule cells |
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Authors: | Kaseda Ryohei Iino Noriaki Hosojima Michihiro Takeda Tetsuro Hosaka Kiyoko Kobayashi Asako Yamamoto Keiko Suzuki Akiyo Kasai Ayaka Suzuki Yoshiki Gejyo Fumitake Saito Akihiko |
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Institution: | Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Niigata 951-8510, Japan. |
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Abstract: | Serum levels of cystatin C, an endogenous cysteine proteinase inhibitor, are often used as an indicator of glomerular filtration rate. Although it is known that cystatin C is filtered by glomeruli and metabolized in proximal tubule cells (PTC), the precise molecular mechanism underlying this process is undetermined. Using quartz-crystal microbalance analyses, we demonstrate that cystatin C binds directly to megalin, an endocytic receptor in PTC, in a Ca(+)-dependent manner. We also find that cystatin C is endocytosed specifically via megalin in rat yolk sac epithelium-derived L2 cells which share a variety of characteristics with PTC. Finally, in vivo studies using kidney-specific megalin knockout mice provide evidence that megalin mediates proximal tubular uptake of cystatin C. We conclude that megalin is an endocytic receptor of cystatin C in PTC. |
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Keywords: | Chronic kidney disease Cystatin C Cysteine proteinase inhibitor Endocytosis Glomerular filtration rate Megalin Proximal tubule cell Quartz-crystal microbalance |
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