Published online before print July 3, 2008

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.080063

Accepted for publication April 9, 2008.

Article

Selective Loss of Podoplanin Protein Expression Accompanies Proteinuria and Precedes Alterations in Podocyte Morphology in a Spontaneous Proteinuric Rat Model

Klaas Koop^*@, Michael Eikmans, Markus Wehland, Hans Baelde^*, Daphne Ijpelaar^*, Reinhold Kreutz, Hiroshi Kawachi, Dontscho Kerjaschki^¶, Emile de Heer^*, and Jan Anthonie Bruijn^*

From the Departments of Pathology* and Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands; the Department of Clinical Pharmacology and Toxicology, Charité Universitätsmedizin Berlin, Berlin, Germany; the Department of Cell Biology, Division of Nephrology, Faculty of Medicine, Niigata University, Niigata, Japan; and the Clinical Institute of Pathology,^¶ Vienna Medical University, Vienna, Austria

^@ To whom correspondence should be addressed. E-mail: k.koop{at}lumc.nl.

	Abstract

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 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.