Megalin-mediated endocytosis of cystatin C in proximal tubule cells.
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.
Kaseda
Ryohei
R
Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Niigata 951-8510, Japan.
Iino
Noriaki
N
Hosojima
Michihiro
M
Takeda
Tetsuro
T
Hosaka
Kiyoko
K
Kobayashi
Asako
A
Yamamoto
Keiko
K
Suzuki
Akiyo
A
Kasai
Ayaka
A
Suzuki
Yoshiki
Y
Gejyo
Fumitake
F
Saito
Akihiko
A
D000818:Animals; D002460:Cell Line; D055316:Cystatin C; D015891:Cystatins / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051381:Rats
C525031:Cst3 protein, mouse; C525032:Cst3 protein, rat; D055316:Cystatin C; D015891:Cystatins; D026561:Low Density Lipoprotein Receptor-Related Protein-2; C055127:Lrp2 protein, mouse