Podocytes express ADAMTS13 in normal renal cortex and in patients with thrombotic thrombocytopenic purpura
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Podocytes express ADAMTS13 in normal renal cortex and in patients with thrombotic thrombocytopenic purpura. / Manea, Minola; Kristoffersson, AnnCharlotte; Schneppenheim, Reinhard; Saleem, Moin A; Mathieson, Peter W; Mörgelin, Matthias; Björk, Peter; Holmberg, Lars; Karpman, Diana.
in: BRIT J HAEMATOL, Jahrgang 138, Nr. 5, 09.2007, S. 651-62.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Podocytes express ADAMTS13 in normal renal cortex and in patients with thrombotic thrombocytopenic purpura
AU - Manea, Minola
AU - Kristoffersson, AnnCharlotte
AU - Schneppenheim, Reinhard
AU - Saleem, Moin A
AU - Mathieson, Peter W
AU - Mörgelin, Matthias
AU - Björk, Peter
AU - Holmberg, Lars
AU - Karpman, Diana
PY - 2007/9
Y1 - 2007/9
N2 - Congenital thrombotic thrombocytopenic purpura (TTP) is associated with ADAMTS13 mutations. The major site of ADAMTS13 synthesis is the liver. Expression in other tissues, and in TTP, has not been shown. In this study, ADAMTS13 protein expression was investigated in normal kidney and in renal tissue from two TTP patients, with a compound heterozygous mutation (P353L and P457L) and a homozygous mutation (4143insA). Real-time polymerase chain reaction demonstrated ADAMTS13 mRNA in normal kidney. ADAMTS13 was detected in the glomeruli and tubuli of normal and TTP kidney using anti-ADAMTS13 antibodies. In the glomeruli, expression was localised to podocytes (as demonstrated by counterstaining with two podocyte markers) and endothelium. Similar distribution was detected in the TTP kidneys. Electron microscopy detected ADAMTS13 in podocytes, endothelium and glomerular basement membrane. Cultured human podocytes expressed ADAMTS13 mRNA and protein, and podocyte lysate exhibited von Willebrand factor-cleaving activity. Mutation expression studies of the P353L and P457L mutations showed partially impaired secretion and lower activity of the secreted mutants. Impaired secretion has previously been shown for the 4143insA mutation. Podocyte-derived ADAMTS13 may offer local protection in the high-shear microcirculation of the glomerulus. The mutations in the two TTP patients studied enabled protein expression in the podocytes but affected protease secretion.
AB - Congenital thrombotic thrombocytopenic purpura (TTP) is associated with ADAMTS13 mutations. The major site of ADAMTS13 synthesis is the liver. Expression in other tissues, and in TTP, has not been shown. In this study, ADAMTS13 protein expression was investigated in normal kidney and in renal tissue from two TTP patients, with a compound heterozygous mutation (P353L and P457L) and a homozygous mutation (4143insA). Real-time polymerase chain reaction demonstrated ADAMTS13 mRNA in normal kidney. ADAMTS13 was detected in the glomeruli and tubuli of normal and TTP kidney using anti-ADAMTS13 antibodies. In the glomeruli, expression was localised to podocytes (as demonstrated by counterstaining with two podocyte markers) and endothelium. Similar distribution was detected in the TTP kidneys. Electron microscopy detected ADAMTS13 in podocytes, endothelium and glomerular basement membrane. Cultured human podocytes expressed ADAMTS13 mRNA and protein, and podocyte lysate exhibited von Willebrand factor-cleaving activity. Mutation expression studies of the P353L and P457L mutations showed partially impaired secretion and lower activity of the secreted mutants. Impaired secretion has previously been shown for the 4143insA mutation. Podocyte-derived ADAMTS13 may offer local protection in the high-shear microcirculation of the glomerulus. The mutations in the two TTP patients studied enabled protein expression in the podocytes but affected protease secretion.
KW - ADAM Proteins
KW - Adult
KW - Child, Preschool
KW - Female
KW - Gene Expression
KW - Glomerular Basement Membrane
KW - Humans
KW - Kidney Cortex
KW - Microscopy, Electron
KW - Mutation
KW - Podocytes
KW - Polymerase Chain Reaction
KW - Purpura, Thrombotic Thrombocytopenic
KW - RNA, Messenger
U2 - 10.1111/j.1365-2141.2007.06694.x
DO - 10.1111/j.1365-2141.2007.06694.x
M3 - SCORING: Journal article
C2 - 17627784
VL - 138
SP - 651
EP - 662
JO - BRIT J HAEMATOL
JF - BRIT J HAEMATOL
SN - 0007-1048
IS - 5
ER -