Selective loss of podoplanin protein expression accompanies proteinuria and precedes alterations in podocyte morphology in a spontaneous proteinuric rat model.
To evaluate changes during the development of proteinuria, podocyte morphology and protein expression were evaluated in spontaneously proteinuric, Dahl salt-sensitive (Dahl SS) rats. Dahl SS rats on a low-salt diet were compared with spontaneously hypertensive rats (SHR) at age 2, 4, 6, 8, and 10 weeks. Blood pressure, urinary protein excretion, urinary albumin excretion, and podocyte morphology were evaluated. In addition, the expression of 11 podocyte-related proteins was determined by analyzing protein and mRNA levels. In Dahl SS rats, proteinuria became evident around week 5, increasing thereafter. SHR rats remained non-proteinuric. Dahl SS rats showed widespread foot process effacement at 10 weeks. At < or =8 weeks, expression and distribution of the podocyte proteins was similar between the two strains, except for the protein podoplanin. At 4 weeks, podoplanin began decreasing in the glomeruli of Dahl SS rats in a focal and segmental fashion. Podoplanin loss increased progressively and correlated with albuminuria (r = 0.8, P < 0.001). Double labeling experiments revealed increased expression of the podocyte stress marker desmin in glomerular areas where podoplanin was lost. Dahl SS rats did not show podoplanin gene mutations or decreased mRNA expression. Thus, podocyte morphology and the expression and distribution of most podocyte-specific proteins were normal in young Dahl SS rats, despite marked proteinuria. Our study suggests that decreased expression of podoplanin plays a role in the decrease of glomerular permselectivity.
Koop
Klaas
K
Department of Pathology, Leiden University Medical Center, Building 1, L1-Q, PO BOX 9600, 2300 RC Leiden, The Netherlands. k.koop@lumc.nl
Eikmans
Michael
M
Wehland
Markus
M
Baelde
Hans
H
Ijpelaar
Daphne
D
Kreutz
Reinhold
R
Kawachi
Hiroshi
H
Kerjaschki
Dontscho
D
de Heer
Emile
E
Bruijn
Jan Anthonie
JA
D000367:Age Factors; D000818:Animals; D001794:Blood Pressure; D002452:Cell Count; D003893:Desmin / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D010539:Permeability; D050199:Podocytes / Q000378:metabolism / Q000473:pathology*; D011507:Proteinuria / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D020303:Rats, Inbred Dahl; D011918:Rats, Inbred SHR; D000098853:Podoplanin
D003893:Desmin; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; C092025:Pdpn protein, rat; D000098853:Podoplanin