Connective tissue growth factor expression in the rat remnant kidney model and association with tubular epithelial cells undergoing transdifferentiation.
Connective tissue growth factor (CTGF) has been shown to mediate many actions of transforming growth factor-beta (TGF-beta) in the fibrotic response in several diseases. We compared expression of CTGF, TGF-beta, platelet-derived growth factor (PDGF), TNF-alpha, and interleukin-1 (IL-1) by in situ hybridization in Sprague-Dawley rats euthanized at 0, 2, 4, and 8 weeks after 5/6 nephrectomy using the rat remnant kidney model of renal failure. Collagen was evaluated by trichrome stains, immunohistochemistry, and electron microscopy. We compared expression patterns to cells undergoing metaplasia. Tubular epithelial regeneration and transdifferentiation to myofibroblasts were assessed morphologically and by proliferating cell nuclear antigen, smooth muscle actin, desmin, and vimentin immunohistochemistry. CTGF expression was minimal in controls, mild at 2 weeks and marked by 4 to 8 weeks in interstitial fibroblasts, coinciding with damage, regeneration, and fibrosis. TGF-beta expression was increased in many cell types at 2 weeks, increased further by 4 weeks, then remained constant. PDGF-B messenger RNA was found in many stromal cells at 2-4 weeks, but expression decreased at 8 weeks. No significant IL-1 or TNF-alpha staining was detected. We conclude that CTGF and interacting factors are associated with development or progression of chronic interstitial fibrosis. Proximity of CTGF, TGF-beta, and PDGF mRNA expression to regenerative epithelial cells and those transdifferentiating to myofibroblasts suggests that growth factors may modulate renal tubular epithelial differentiation.
Frazier
K S
KS
College of Veterinary Medicine, Veterinary Diagnostic and Investigational Laboratory, The University of Georgia, Tifton 31793, USA. kfrazier@tifton.cpes.peachnet.edu
Paredes
A
A
Dube
P
P
Styer
E
E
D000818:Animals; D002454:Cell Differentiation; D055513:Connective Tissue Growth Factor; D003893:Desmin / Q000032:analysis; D004195:Disease Models, Animal; D006133:Growth Substances / Q000096:biosynthesis*; D017874:Immediate-Early Proteins / Q000096:biosynthesis*; D017403:In Situ Hybridization / Q000662:veterinary; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1 / Q000096:biosynthesis; D007668:Kidney / Q000378:metabolism*; D007674:Kidney Diseases / Q000473:pathology / Q000662:veterinary*; D007684:Kidney Tubules / Q000502:physiology; D009392:Nephrectomy / Q000662:veterinary; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration; D012376:Rodent Diseases / Q000378:metabolism / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C526316:CCN2 protein, rat; D003893:Desmin; D006133:Growth Substances; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D055513:Connective Tissue Growth Factor