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EphB4 forward signalling maintains podocyte homeostasis during Thy1.1 nephritis

Wnuk, Monika and Hlushchuk, Ruslan and Tuffin, Gerald and Martiny-Baron, Georg and Holzer, Philipp and Imbach, Patricia and Djonov, Valentin and Huynh-Do, Uyen (2012) EphB4 forward signalling maintains podocyte homeostasis during Thy1.1 nephritis. Journal of American Society of Nephrology, 81 (12). pp. 1212-1225. ISSN 00852538

Abstract

Eph receptor tyrosine kinases and their ligands (ephrins) play a pivotal role in maintaining homeostasis of many adult organs and are also widely expressed in the adult kidney. The aim of our study was therefore to assess their role in the glomerular recovery from Thy 1.1 nephritis, a rat model of reversible mesangioproliferative glomerulonephritis (GN).
EphB4 and ephrinBs were expressed in healthy glomeruli and upregulated during the course of Thy1.1 nephritis. EphB4 was predominantly expressed at the apical membranes of podocytes, whereas ephrinBs were located at podocyte foot processes in healthy and nephritic glomeruli. Although EphB4 was constitutively expressed in the glomeruli, its forward signalling was initiated specifically around day 9 of nephritis. To dissect its role during the course of acute GN, we applied NVP-BHG712, a novel small molecular weight inhibitor of EphB4 phosphorylation, or vehicle to nephritic rats. Morphological evidence of podocyte injury was not detected in vehicle-treated nephritic rats and podocyte number in this group was not different from healthy controls. On the other hand, NVP-BHG712 application resulted in glomerular microaneurysm formation and podocyte damage, such as the formation of apical openings, pseudocysts and absorption droplets. Podocyte loss due to EphB4 inhibition was partially due to apoptosis. Additionally, NVP-BHG712 application to nephritic rats reduced the onset of intussusceptive angiogenesis suggesting a previously unrecognized role of podocytes in regulating intussusceptive vessel splitting.

Item Type: Article
Keywords: podocyte homeostasis, EphB4 forward signalling, nephritis, glomerular recovery
Date Deposited: 26 Apr 2016 23:46
Last Modified: 26 Apr 2016 23:46
URI: https://oak.novartis.com/id/eprint/2639

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