The membrane attack complex, C5b-9, up regulates collagen gene expression in renal tubular epithelial cells.
Evidence suggesting a direct role for proteinuria in the pathogenesis of renal tubulointerstitial fibrosis is accumulating. However the mechanism by which proteinuria leads to injury is unknown. In proteinuric states complement proteins are filtered through the glomerulus and could contribute to the tubular damage. The aim of this study was to investigate the role of complement activation in the progression of interstitial fibrosis. To determine whether complement activation may be responsible for the pro-fibrotic response that occurs in the tubulointerstitial compartment we stimulated primary cultures of proximal tubular epithelial cells with membrane attack complex, C5b-9. This led to increased mRNA concentrations of both collagen type IV and its intracellular chaperone, Heat Shock Protein 47 (HSP47). To determine whether this occurred in vivo Adriamycin was used to induce proteinuria in female Balb/c mice. The expression of collagen type IV and HSP47 was increased in proteinuric mice compared to control mice. In proteinuric mouse kidney, C3 was deposited at sites of tubulointerstitial injury and there was a relationship between C3 deposition and immunochemical staining for collagen type IV and HSP47. In situ hybridization suggested that the renal tubular epithelium was actively expressing HSP47 mRNA and, by implication, excess collagen. These observations support the hypothesis that complement activation on tubular epithelial cells can directly increase the pro-fibrotic process associated with tubulointerstitial damage.
Abe
K
K
Department of Nephrology and Transplantation, Guy's, King's and St Thomas' School of Medicine, Dentistry and Biomedical Science, King's College London, UK.
Li
K
K
Sacks
S H
SH
Sheerin
N S
NS
D000419:Albuminuria / Q000276:immunology / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis*; D015938:Complement Membrane Attack Complex / Q000276:immunology*; D004317:Doxorubicin; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D050958:HSP47 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics; D007684:Kidney Tubules / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009395:Nephritis, Interstitial / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000276:immunology
D015938:Complement Membrane Attack Complex; D050958:HSP47 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D012333:RNA, Messenger; C494661:Serpinh1 protein, mouse; D004317:Doxorubicin; D003094:Collagen