Relationship between vimentin expressing renal tubules and interstitial fibrosis in chronic progressive nephropathy in aged rats.
We investigated the relationship between regenerating renal tubular epithelial cells and myofibroblast development in chronic progressive nephropathy (CPN) of aged male F344 rats. We used established criteria to classify disease in rats with CPN as grade 1 (n=9), grade 2 (n=10), grade 3 (n=7) and grade 4 (n=4). Five young rats served as controls (grade 0). The ratio of fibrotic tissues per unit area, assessed in collagen type III-immunostained sections by morphometric analysis, increased significantly with advancing grade of CPN. Vimentin-expressing, regenerating renal tubules were found from grade 1 and continued to increase in number up to grade 3, decreasing slightly, however, in grade 4. Similar kinetics were seen for the number of alpha-smooth muscle actin-positive myofibroblasts, and there was a significant correlation between the number of regenerating renal tubules and myofibroblast development (correlation coefficient=0.83, P<0.01). The myofibroblasts developed in close association with the fibrotic areas seen in grades 1-4; the cells also reacted to desmin or vimentin, indicating the activated state. Immunohistochemistry for platelet-derived growth factor (PDGF)-BB and transforming growth factor (TGF)-beta revealed that vimentin-positive renal tubules were positive for PDGF-BB, but negative for TGF-beta, and that interstitial reactive cells showed no positive reactions for both factors. The present studies on rat CPN showed that regenerating renal tubules may be a major source of a fibrogenic growth factor, PDGF-BB, and that the PDGF-BB might induce the development of fibrogenic cells, myofibroblasts, culminating in progressive interstitial fibrosis.
Nakatsuji
S
S
Department of Toxicology, New Drug R&D Centre, Kanebo Ltd., Osaka, Japan.
Yamate
J
J
Sakuma
S
S
D000199:Actins / Q000378:metabolism; D000818:Animals; D000077214:Becaplermin; D002908:Chronic Disease; D003094:Collagen / Q000378:metabolism; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D005355:Fibrosis / Q000473:pathology; D007124:Immunoenzyme Techniques; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009395:Nephritis, Interstitial / Q000378:metabolism* / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D011916:Rats, Inbred F344; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism*
D000199:Actins; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D016212:Transforming Growth Factor beta; D014746:Vimentin; D000077214:Becaplermin; D003094:Collagen