Complement membrane attack complex (C5b-9) mediates interstitial disease in experimental nephrotic syndrome.

Abstract

Accumulating evidence suggests that the generation of complement activation products from filtered complement components in urine with nonselective proteinuria leads to tubulointerstitial disease, resulting in progressive loss of renal function. To elucidate the role of C5b-9 in complement-mediated effects on renal tubular cells exposed to proteinuric urine, equivalent levels of proteinuria were induced (using the aminonucleoside of puromycin) in normocomplementemic and genetically C6-deficient piebald viral glaxo (PVG) rats. Semiquantitative histologic analysis revealed that complement-sufficient animals developed more severe tubulointerstitial disease than did C6-deficient rats. Amelioration of tubulointerstitial damage in C6-deficient animals was confirmed by studies with three independent markers of tubular damage, i.e., vimentin, osteopontin, and proliferating cell nuclear antigen. More tubular epithelial cells expressed osteopontin (an early marker of tubular injury) in normocomplementemic rats, compared with C6-deficient rats, at both days 7 and 12. Staining of vimentin in the tubules, near areas of tubular damage, was increased in normocomplementemic rats at day 12, and more proliferating cell nuclear antigen-positive tubular cells were observed at day 12 in complement-sufficient animals. The tubulointerstitial damage in complement-sufficient rats was also associated with greater accumulation of extracellular matrix (fibronectin) at day 12. These studies document for the first time an important role for C6, and therefore C5b-9, in the pathogenesis of nonimmunologic tubulointerstitial injury induced by proteinuria. These findings suggest that C5b-9 formation resulting from proteinuria contributes to the loss of nephron function by damaging the tubulointerstitium and that prevention of C5b-9 formation in tubules could slow the deterioration of renal function.

• Authors: M Nangaku, J Pippin, W G Couser
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 10 Issue 11 Pg. 2323-31 (Nov 1999) ISSN: 1046-6673 [Print] United States
• PMID: 10541291 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Complement C6
• Complement Membrane Attack Complex
• Fibronectins
• Vimentin

Topics

• Animals
• Complement C6 (deficiency, physiology)
• Complement Membrane Attack Complex (physiology)
• Fibronectins (biosynthesis)
• Kidney Tubules (pathology)
• Male
• Nephrotic Syndrome (metabolism, pathology)
• Proteinuria (metabolism, pathology)
• Rats
• Vimentin (biosynthesis)