Absence of decorin adversely influences tubulointerstitial fibrosis of the obstructed kidney by enhanced apoptosis and increased inflammatory reaction.
Decorin, a small dermatan-sulfate proteoglycan, participates in extracellular matrix assembly and influences directly and indirectly cell behavior via interactions with signaling membrane receptors and transforming growth factor (TGF)-beta. We have therefore compared the development of tubulointerstitial kidney fibrosis in wild-type (WT) and decorin-/- mice in the model of unilateral ureteral obstruction. Without obstruction, kidneys from decorin-/- mice did not differ in any aspect from their WT counterparts. However, already 12 hours after obstruction decorin-/- animals showed lower levels of p27(KIP1) and soon thereafter a more pronounced up-regulation and activation of initiator and effector caspases followed by enhanced apoptosis of tubular epithelial cells. Later, a higher increase of TGF-beta1 became apparent. After 7 days, there was an up to 15-fold transient up-regulation of the related proteoglycan biglycan, which was mainly caused by the appearance of biglycan-expressing mononuclear cells. Other small proteoglycans showed no similar response. Because of enhanced degradation of type I collagen, end-stage kidneys from decorin-/- animals were more atrophic than WT kidneys. These data suggest that decorin exerts beneficial effects on tubulointerstitial fibrosis, primarily by influencing the expression of a key cyclin-dependent kinase inhibitor and by limiting the degree of apoptosis, mononuclear cell infiltration, tubular atrophy, and expression of TGF-beta1.
Schaefer
Liliana
L
Department of Internal Medicine D, Physiological Chemistry and Pathobiochemistry, and Arteriosclerosis Research, University of Münster, Münster, Germany. schaefl@uni-muenster.de
Macakova
Katarina
K
Raslik
Igor
I
Micegova
Miroslava
M
Gröne
Hermann-Josef
HJ
Schönherr
Elke
E
Robenek
Horst
H
Echtermeyer
Frank G
FG
Grässel
Susanne
S
Bruckner
Peter
P
Schaefer
Roland M
RM
Iozzo
Renato V
RV
Kresse
Hans
H
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D058575:Decorin; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins; D005355:Fibrosis; D017353:Gene Deletion; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D011509:Proteoglycans / Q000235:genetics*
C546879:Dcn protein, mouse; D058575:Decorin; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans