Permeability, ultrastructural changes, and distribution of novel proteins in the glomerular barrier in early puromycin aminonucleoside nephrosis.
OBJECTIVE
It is still unclear what happens in the glomerulus when proteinuria starts. Using puromycin aminonucleoside nephrosis (PAN) rats, we studied early ultrastructural and permeability changes in relation to the expression of the podocyte-associated molecules nephrin, α-actinin, dendrin, and plekhh2, the last two of which were only recently discovered in podocytes.


METHODS
Using immune stainings, semiquantitative measurement was performed under the electron microscope. Permeability was assessed using isolated kidney perfusion with tracers. Possible effects of ACE inhibition were tested.


RESULTS
By day 2, some patchy foot process effacement, but no proteinuria, appeared. The amount of nephrin was reduced in both diseased and normal areas. The other proteins showed few changes, which were limited to diseased areas. By day 4, foot process effacement was complete and proteinuria appeared in parallel with signs of size barrier damage. Nephrin decreased further, while dendrin and plekhh2 also decreased but α-actinin remained unchanged. ACE inhibition had no significant protective effect.


CONCLUSIONS
PAN glomeruli already showed significant pathology by day 4, despite relatively mild proteinuria. This was preceded by altered nephrin expression, supporting its pivotal role in podocyte morphology. The novel proteins dendrin and plekhh2 were both reduced, suggesting roles in PAN, whereas α-actinin was unchanged.
Dunér
Fredrik
F
Departmentsof Clinical Science, Division of Renal Medicine, Karolinska Institutet, Stockholm, Sweden. fredrik.duner @ ki.se
Lindström
Karin
K
Hultenby
Kjell
K
Hulkko
Jenny
J
Patrakka
Jaakko
J
Tryggvason
Karl
K
Haraldsson
Börje
B
Wernerson
Annika
A
Pettersson
Erna
E
D000185:Actinin / Q000096:biosynthesis; D000818:Animals; D007674:Kidney Diseases / Q000473:pathology / Q000503:physiopathology*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000648:ultrastructure*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D009401:Nephrosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D010539:Permeability; D011506:Proteins / Q000378:metabolism; D011507:Proteinuria / Q000503:physiopathology*; D011692:Puromycin Aminonucleoside; D051381:Rats; D017207:Rats, Sprague-Dawley
D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; C104328:dendrin; C113267:nephrin; C554922:plekhh2 protein, rat; D000185:Actinin; D011692:Puromycin Aminonucleoside