Expression of podocyte-associated molecules in acquired human kidney diseases.
Proteinuria is a poorly understood feature of many acquired renal diseases. Recent studies concerning congenital nephrotic syndromes and findings in genetically modified mice have demonstrated that podocyte molecules make a pivotal contribution to the maintenance of the selective filtration barrier of the normal glomerulus. However, it is unclear what role podocyte molecules play in proteinuria of acquired renal diseases. This study investigated the mRNA and protein expression of several podocyte-associated molecules in acquired renal diseases. Forty-eight patients with various renal diseases were studied, including minimal change nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, lupus nephritis, and diabetic nephropathy, together with 13 kidneys with normal glomerular function. Protein levels of nephrin, podocin, CD2-associated protein, and podocalyxin were investigated using quantitative immunohistochemical assays. Real-time PCR was used to determine the mRNA levels of nephrin, podocin, and podoplanin in microdissected glomeruli. The obtained molecular data were related to electron microscopic ultrastructural changes, in particular foot process width, and to clinical parameters. In most acquired renal diseases, except in IgA nephropathy, a marked reduction was observed at the protein levels of nephrin, podocin, and podocalyxin, whereas an increase of the glomerular mRNA levels of nephrin, podocin, and podoplanin was found, compared with controls. The mean width of the podocyte foot processes was inversely correlated with the protein levels of nephrin (r = -0.443, P < 0.05), whereas it was positively correlated with podoplanin mRNA levels (r = 0.468, P < 0.05) and proteinuria (r = 0.585, P = 0.001). In the diseases studied, the decrease of slit diaphragm proteins was related to the effacement of foot processes and coincided with a rise of the levels of the corresponding mRNA transcripts. This suggests that the alterations in the expression of podocyte-associated molecules represent a compensatory reaction of the podocyte that results from damage associated with proteinuria.
Koop
Klaas
K
Departments of Pathology and Nephrology, Leiden University Medical Center, Leiden, The Netherlands. k.koop@lumc.nl
Eikmans
Michael
M
Baelde
Hans J
HJ
Kawachi
Hiroshi
H
De Heer
Emile
E
Paul
Leendert C
LC
Bruijn
Jan A
JA
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D015153:Blotting, Western; D018801:CD2 Antigens / Q000096:biosynthesis; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary / Q000378:metabolism; D005260:Female; D005922:Glomerulonephritis, IGA / Q000473:pathology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000166:cytology* / Q000378:metabolism* / Q000648:ultrastructure; D007674:Kidney Diseases / Q000378:metabolism*; D008181:Lupus Nephritis / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D015233:Models, Statistical; D015345:Oligonucleotide Probes / Q000494:pharmacology; D014176:Protein Biosynthesis; D011506:Proteins; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000096:biosynthesis
D048868:Adaptor Proteins, Signal Transducing; D018801:CD2 Antigens; C114545:CD2-associated protein; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D015345:Oligonucleotide Probes; D011506:Proteins; D012333:RNA, Messenger; D012795:Sialoglycoproteins; C113267:nephrin; C001643:podocalyxin; D012313:RNA