Role of renal tubular CD44s/CD44v3 expression in LPS-induced renal injury
Projectomschrijving
2013 Ronde Kennisinfrastructuur (publiceren van negatieve of neutrale dierexperimentele data):
Deze studie had als brede doelstelling om interventiemogelijkheden te ontwikkelen ter preventie of behandeling van nierschade. Er is gekeken naar de rol van het eiwit CD44v3, een bepaalde vorm van het eiwit CD44, bij de bescherming van de nieren na bloedvergiftiging. In de gebruikte celkweken bleek CD44v3 zoals verwacht de functie van nierbeschermende factoren te bevorderen. In het onderzochte diermodel, waarbij genetisch gemodificeerde muizen werden gebruikt die CD44v3 in de nierbuizen tot expressie brachten, werd daarentegen geen beschermende rol van CD44v3 gevonden. De onderzoekers willen deze resultaten publiceren in een internationaal tijdschrift.
Verslagen
Samenvatting van de aanvraag
CD44 is a broadly distributed transmembrane receptor encoded by a single gene of 20 exons, of which 10 are variants alternatively spliced generating several isoforms with a different extracellular domain. CD44standard/CD44s is the shortest and most common isoform largely expressed by hematopoietic cells, whereas CD44variant3-10/CD44v3 is a larger molecule with heparan sulphate side chains that enable the binding to several molecules including HGF, HB-EGF. A considerable number of studies showed a crucial role for CD44 in inflammatory disorders, including renal inflammatory diseases and endotoxic shock-induced organ failure.
Normally in kidneys CD44 is found on passenger leukocytes; however, in inflammatory renal diseases, CD44-isoforms expression is markedly enhanced, particularly in crescents and injured proximal epithelial tubules (TEC). Our previous studies showed that CD44 tubular expression-rate closely correlates with inflammation and tubular damage, and absence of CD44 ameliorates ischemia-reperfusion-induced AKI.
In order to assess the function of CD44 de novo expression on renal tubules upon inflammation and particularly SIRS-induced renal injury, we used unique transgenic mice that specifically overexpress either CD44s or CD44v3 on TEC and subjected them to intraperitoneal injection of lipopolysaccharide (LPS). We hypothesized that the tubular overexpression of differential CD44-isoforms would affect the progression of renal inflammation and injury/function upon endotoxin shock, and that the presence of CD44v3 would ameliorate AKI due to its ability to bind and facilitate the signalling of the anti-inflammatory and protective factor HGF.