Increased expression of decorin in experimental hydronephrosis.
Transforming growth factor (TGF)-beta1 is a potential mediator of tubulointerstitial (TI) fibrosis in the rat unilateral ureteral obstruction (UUO) model. Decorin is a protein composed of a core protein and a chondroitin sulfate side chain and is capable of inactivating TGF-beta. Since TGF-beta strongly induces the synthesis of decorin in experimental glomerulonephritis, it was our intent to investigate whether altered decorin expression is operant in the rat UUO model. Renal cortical decorin mRNA levels initially became elevated (2.5-fold) in obstructed kidney (OBK) versus contralateral unobstructed kidney (CUK) 24 hours post-UUO and remained greater in the OBK specimens at 48 (2.3-fold), 96 (2.2-fold), and 168 (1.9-fold) hours post-ureteral ligation. Whole-body X-irradiation 11 days prior to UUO significantly reduced decorin mRNA at 24 and 96 hours post-UUO. On immunolabeling, decorin was only evident in the adventitia of blood vessels in CUK specimens at any time point after UUO. In contrast, OBK specimens initially demonstrated periglomerular and peritubular interstitial localization of decorin at 96 hours post-ureteral ligation, which became even more intense and diffuse in the tubulointerstitium at 168 hours post-UUO. On Western analysis, there were highly significant increases in decorin protein expression in the OBK versus the CUK specimens at 96 and 168 hours post-UUO. Levels of active TGF-beta1 in the renal cortex of OBK were 1.9- and 3.6-fold higher than CUK at 48 and 96 hours post-UUO. In summary, we demonstrated that post-UUO, decorin mRNA and protein expression is up-regulated in the renal cortex of OBK, but not CUK, specimens in a temporal parallel with active TGF-beta1 levels and macrophage infiltration. We postulate that the development of TI fibrosis in this model may be related to only a physiologic induction of decorin by TGF-beta, and that pharmacologic levels may be required to retard or prevent scarring via TGF-beta inhibition.
Diamond
J R
JR
Department of Medicine, Milton S. Hershey Medical Center and Pennsylvania State University College of Medicine, 17033, USA.
Levinson
M
M
Kreisberg
R
R
Ricardo
S D
SD
D000818:Animals; D017077:Culture Media, Conditioned; D058575:Decorin; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins; D005355:Fibrosis; D006869:Hydronephrosis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007672:Kidney Cortex / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008297:Male; D011509:Proteoglycans / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation; D014517:Ureteral Obstruction / Q000150:complications; D014916:Whole-Body Irradiation
D017077:Culture Media, Conditioned; C546880:Dcn protein, rat; D058575:Decorin; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta