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Vasodilator-Stimulated Phosphoprotein–Deficient Mice Demonstrate Increased Platelet Activation but Improved Renal Endothelial Preservation and Regeneration in Passive Nephrotoxic Nephritis

Bernd Hohenstein^*, Laura Kasperek, Dieter-Johannes Kobelt^*, Christoph Daniel^*, Stepan Gambaryan, Thomas Renné, Ulrich Walter, Kerstin U. Amann and Christian P.M. Hugo^*

Divisions of ^* Nephrology and Pathology, University Erlangen-Nuremberg, Erlangen; and the Institute of Clinical Biochemistry and Pathobiochemistry, University Wuerzburg, Wuerzburg, Germany

Address correspondence to: Dr. Christian Hugo, Department of Nephrology, University Erlangen-Nuremberg, Loschgestrasse 8, Erlangen 91054, Germany. Phone: 49-9131-8539002; Fax: 49-9131-8539209l christian.hugo{at}rzmail.uni-erlangen.de

Received for publication July 23, 2004. Accepted for publication January 11, 2005.

Vasodilator-stimulated phosphoprotein (VASP), an actin cytoskeletal protein, is expressed in various cell types including renal cells. In vitro studies provide evidence for a role of VASP regarding platelet activation, cell adhesion, migration, and capillary formation. The in vivo role of VASP was investigated in experimental inflammatory renal disease. Kidneys of healthy VASP deficient (–/–) and wild-type (wt) mice were compared regarding morphology and functional parameters. Passive nephrotoxic nephritis was induced in 28 VASP –/– and 28 wt mice; kidneys were harvested; and tissues were analyzed by morphometric, immunohistochemical, and electron microscopic techniques on days 3, 7, 14, and 28. The time course of disease in VASP –/– mice differed substantially and biphasically from that in wt controls. Early on, VASP –/– mice demonstrated increased platelet influx associated with augmented glomerular and tubulointerstitial inflammation and sclerosis. Whereas renal disease continuously worsened up to day 28 in wt controls, renal disease in VASP –/– mice hardly progressed after day 3 as assessed by various injury indices. This long-term improvement of renal histology in VASP –/– compared with wt mice was associated with remarkable capillary preservation/regeneration up to day 28 mediated via an increased proliferative and a reduced apoptotic activity of VASP-negative peritubular endothelial cells. Despite an enhanced injury response early on, VASP –/– mice are protected from long-term progression of nephrotoxic nephritis, which is associated with improved renal endothelial cell preservation and regeneration.

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