Evolution of tubulointerstitial fibrosis in experimental renal infection and scarring.
Renal tubulointerstitial fibrosis may result from a loss of tubulointerstitial volume, which produces a disproportionate increase in the density of matrix. This study examines the relationship between fibrogenesis and collapse in scar formation after experimental renal infection. Escherichia coli were inoculated into the renal cortex of Sprague Dawley rats, with saline substituted in a control group. Glomerular, tubular, and interstitial profile areas were determined. Density of glomerular profiles was used as a measure of tubulointerstitial collapse. Collagen type I, III, and IV expression was examined by in situ hybridization and immunohistochemistry. Myofibroblasts were identified by alpha smooth muscle actin immunohistochemistry, and matrix metalloproteinase-1 (MMP-1) and MMP-2 were localized with appropriate antisera. Acute interstitial edema was followed by increasing density of glomerular profiles, paralleled by loss of interstitial volume and progressive tubular atrophy. Glomerular profile area remained unchanged. Density of glomerular profiles was not temporally related to myofibroblast accumulation. Procollagen alpha 1(I), alpha 1(III), and alpha 1(IV) transcription was focal, spatially related but temporally ordered. Collagen I, III, and IV immunostaining was increased from days 3, 24, and 100, respectively (P < 0.05 versus day 0 and day 100 saline). However, when corrected for glomerular density, collagen I immunostaining decreased between days 24 and 100, whereas collagen III and IV no longer differed from day 0. MMP staining within the lesion was confined to occasional interstitial and epithelial cells throughout. It is concluded that in this model, contraction and collapse of the tubulointerstitial parenchyma has a greater influence than new collagen production on final fibrotic density.
Hewitson
T D
TD
Department of Nephrology, Royal Melbourne Hospital, Australia.
Darby
I A
IA
Bisucci
T
T
Jones
C L
CL
Becker
G J
GJ
D000704:Analysis of Variance; D000818:Animals; D002921:Cicatrix / Q000473:pathology*; D003094:Collagen / Q000032:analysis* / Q000096:biosynthesis; D017364:Collagenases / Q000032:analysis; D046508:Culture Techniques; D004195:Disease Models, Animal; D004927:Escherichia coli Infections; D005260:Female; D005355:Fibrosis / Q000473:pathology; D018093:Gelatinases / Q000032:analysis; D007150:Immunohistochemistry; D020781:Matrix Metalloproteinase 1; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000032:analysis; D009395:Nephritis, Interstitial / Q000382:microbiology / Q000473:pathology*; D011347:Procollagen / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values
D011347:Procollagen; D012333:RNA, Messenger; D003094:Collagen; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1