C5b-9 regulates peritubular myofibroblast accumulation in experimental focal segmental glomerulosclerosis

Abstract

In human focal segmental glomerulosclerosis (FSGS), the tubulointerstitial deposition of the complement (C5b-9) membrane attack complex is correlated with interstitial myofibroblast accumulation and proteinuria. Here, we hypothesized that C5b-9 formation regulates renal myofibroblast accumulation in Adriamycin nephropathy. Adriamycin nephropathy was induced in complement C6-sufficient (C6+) and C6-deficient (C6-) piebold viral glaxo (PVG) rats. Groups of animals (N= 7 to 8 each) were examined on days 21 and 42. A group of C6+ animals, injected with vehicle, served as the control group. C6+ and C6- rats with Adriamycin nephropathy had equivalent proteinuria. C5b-9 deposition was increased and present on the apical surface of proximal tubular epithelial cells (day 21 and 42) and peritubular region (day 42 only) in C6+ rats with Adriamycin nephropathy, and absent in C6- rats. Peritubular myofibroblast accumulation increased in a time-dependent manner in C6+ proteinuric rats (control 1.2 +/- 0.4; Adriamycin nephropathy day 21 11.0 +/- 0.7; Adriamycin nephropathy day 42 19.8 +/- 1.7 cells per high power field). In C6- rats this increase was blunted by 87% and 56% on days 21 and 42, respectively (P < 0.01), and was associated with reduced interstitial extracellular matrix (ECM) deposition. Tubulointerstitial injury, tubular vimentin and interstitial monocyte accumulation were also reduced in C6- rats with Adriamycin nephropathy on day 21, but not at day 42. In contrast, the increase in periglomerular myofibroblast accumulation and glomerulosclerosis in Adriamycin nephropathy were not altered by C6 deficiency. These data suggest that glomerular ultrafiltration of complement components and the intratubular formation of C5b-9 is a specific promotor of peritubular myofibroblast accumulation in FSGS.