Myofibroblast and alpha 1 (III) collagen expression in experimental tubulointerstitial nephritis.
Despite the importance of tubulointerstitial fibrosis as a predictor of renal function in patients with primary glomerular disease, the identity of the cell(s) that is the source of interstitial collagen production remains unknown. The present study was performed to identify the site of alpha 1(III) production during the development of tubulointerstitial fibrosis. We studied a model of experimental tubulointerstitial nephritis associated with puromycin aminonucleoside (PAN) nephrosis. There was a twofold increase in renal cortical alpha 1 (III) mRNA expression coincident with the onset of tubulointerstitial myofibroblasts infiltration in rats with PAN nephrosis beginning on day 6, which increased to a fivefold difference by day 10. There were 60.8 +/- 40.3 myofibroblast/mm2 within the renal tubulointerstitium of rats with PAN nephrosis on day 6 that peaked at 240.2 +/- 11.1 myofibroblast/mm2 on day 14, which then declined to 43.7 +/- 9.8 myofibroblast/mm2 by day 21. By combining in situ hybridization with immunohistochemistry, alpha 1(III) mRNA expression was colocalized to cells that labeled for alpha-smooth muscle actin identifying them as myofibroblasts. Interestingly, the major site of alpha 1(III) mRNA expression shifted to tubuloepithelial cells with the waning of myofibroblast infiltration on day 21. To determine if PDGF-BB induced myofibroblasts to synthesize alpha 1(III) mRNA, we examined kidneys from rats that had been treated with PDGF-BB (5 mg/kg/day). alpha 1(III) mRNA expression also localized to cells that labeled for alpha-smooth muscle actin. These data demonstrate the cellular source of alpha 1(III) production within the renal tubulointerstitium following injury, and suggest that PDGF-BB may be mediating this production.
Tang
W W
WW
Department of Pathology, Amgen Inc., Thousand Oaks, California, USA.
Van
G Y
GY
Qi
M
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D000199:Actins / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D000077214:Becaplermin; D003094:Collagen / Q000096:biosynthesis* / Q000235:genetics*; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology*; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D009395:Nephritis, Interstitial / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D011692:Puromycin Aminonucleoside / Q000633:toxicity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew
D000199:Actins; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D000077214:Becaplermin; D011692:Puromycin Aminonucleoside; D003094:Collagen