title: Possible mechanisms explaining the tendency towards interstitial fibrosis in aristolochic acid-induced acute tubular necrosis.
abstract: BACKGROUND
  We explored possible mechanisms responsible for the inability of plerosis and the tendency towards fibrosis in aristolochic acid-induced acute tubular necrosis (AA-ATN).
  
  
  METHODS
  Renal biopsy tissues from eight AA-ATN cases were examined. Tubulointerstitial injury was semiquantitatively assessed. Immunohistochemical steptavidin-peroxide (SP) methods were used to determine the expressions of proliferating cell nuclear antigen (PCNA), epidermal growth factor (EGF), alpha-smooth muscle actin (alpha-SMA), transforming growth factor-beta(1) (TGF-beta(1)), connecting tissue growth factor (CTGF), fibronectin (FN), collagen III (Col-III), collagen IV (Col-IV), factor VIII-related antigen (VIII-Ag) and vascular endothelial growth factor (VEGF). Ultramicrostructure of endothelial cells and basement membrane of peritubular capillaries (PTC) and glomerular capillaries was detected by electron microscopy. These data were compared with that of 9 cases of antibiotic-induced ATN (a-ATN) and 10 cases of minor mesangioproliferative non-IgA glomerulonephritis, which served as a control group.
  
  
  RESULTS
  In AA-ATN, almost no renal tubular epithelial cells (RTEC) were PCNA-positive (0.01 +/- 0.02%), and EGF expression was considerably decreased (9.55 +/- 7.22%). This was in contrast with the highly active tubular proliferation (PCNA-positive RTEC 47.25 +/- 19.33%, P < 0.05) and increased EGF expression in a-ATN (64.38 +/- 19.22%, P < 0.05). The expression of alpha-SMA in the tubulointerstitium, the number of interstitial TGF-beta(1)-positive cells and the CTGF-positive interstitial area were all increased in both a-ATN and AA-ATN, with no obvious differences between the two groups. With respect to extracellular matrix (ECM) deposition, FN, Col-III and Col-IV were detected only in the interstitium of AA-ATN. PTC lumina were decreased in size and misshapen in the AA-ATN group. Also in AA-ATN, the luminal wall was partially disrupted, endothelial cells were swollen and vacuoles and granules were found in the cell plasma. Parts of the endothelial cells were detached from the tubular basement membrane.
  
  
  CONCLUSIONS
  The strong ability for RTEC repair after acute injury was severely diminished in AA-ATN, and this effect may be partly due to reduced EGF expression. Anti-fibrosis mechanisms may also be impaired in AA-ATN, since both a-ATN and AA-ATN had increased expression of TGF-beta(1) and CTGF, whereas only the latter group showed ECM deposition. Injury and loss of PTC occurred in AA-ATN, and this may contribute to tubulointerstitial damage, the inability of plerosis and the tendency towards fibrosis in this disease.
authors.affiliation: Renal Division, Department of Medicine, First Hospital, and Institute of Nephrology, Peking University, Beijing 100034, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Li
authors.forename: Haiyan
authors.initials: H
authors.lastname: Wang
mesh_terms: D000199:Actins / Q000378:metabolism; D000328:Adult; D034341:Aristolochic Acids / Q000009:adverse effects*; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D055513:Connective Tissue Growth Factor; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000187:drug effects / Q000648:ultrastructure; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007678:Kidney Glomerulus / Q000098:blood supply / Q000187:drug effects / Q000648:ultrastructure*; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism / Q000648:ultrastructure*; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D009153:Mutagens / Q000009:adverse effects*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000199:Actins; D034341:Aristolochic Acids; D015415:Biomarkers; C526317:CCN2 protein, human; D005353:Fibronectins; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009153:Mutagens; D018809:Proliferating Cell Nuclear Antigen; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; C039825:eye-derived growth factor; D055513:Connective Tissue Growth Factor; D005346:Fibroblast Growth Factors; C000228:aristolochic acid I