Fibrotic Mechanisms in Idiopathic Rapidly Progressive Glomerulonephritis: The Role of TGF-β1 and C5b-9

Abstract

Background. Idiopathic IRPGN is a form of renal vasculitis in which a high chronicity index is present despite minimal impairment of renal function. The present study investigated the mechanisms underlining the relatively early appearance of fibrosis. Methods. In all, 34 patients (17 males) with biopsy proven idiopathic RPGN were included. On light microscopy, the percentage and evolution stage of crescents, the presence of glomerular necrosis, the degree or severity of arteriosclerosis, as well as the extent of tubulointerstitial (TIN) infiltration, interstial fibrosis, and tubular atrophy were assessed. Monoclonal antibodies were used to identify infiltrating macrophages, HLA-DR (+), α-SMA (+), and PCNA (+) cells, the expression of the adhesion molecule ICAM-1, the growth factor TGF-β1, and the terminal complement component C5b-9. Results. The presence of glomerular necrosis correlated positively with the number of SMA (+) cells in TIN (p = 0.036). Glomerular TGF-β1 expression had positive correlation with tubular C5b-9 expression. The tubulointerstitial TGF-β1 expression correlated with tubular C5b-9 expression (p = 0.001) and TGF-β1 expression (p = 0.009). Independent factors predicting the severity of renal function impairment were the CRP levels (p = 0.002) and the degree of arteriosclerosis (p = 0.01). CRP levels correlated with the severity of interstitial infiltration and fibrosis (p = 0.02), the expression of TGF-β1 in the glomeruli (p = 0.009) and the interstitial space (p = 0.001), and the intensity of tubular ICAM-1 and C5b-9 expression (p = 0.023, p = 0.002, respectively). The severity of proteinuria showed a significant correlation with the expression of TGF-β1 in the glomeruli (p = 0.033) and the tubulointerstitium (p = 0.019). Conclusions. The activation of interstitial fibroblasts seems to be an early phenomenon that is related to the extent of glomerular necrosis. Glomerular TGF-β1 may induce tubular expression of C5b-9. Increased tubular C5b-9 expression may result in interstitial fibrosis through increased TGF-β1 production.

Complement inhibition in cancer therapy

“…Complement activity also stimulates the expression of transforming growth factor β (TGF-β) [80, 81]. TGF-β displays pro- and anti-tumor effects, depending on the cellular context [82].…”

Complement and macrophage crosstalk during process of angiogenesis in tumor progression

“…In addition, elevated levels of plasma C5a has been reported in Lung cancer [ 5 , 23 ], and in other tissue specific cancers [ 23 , 24 ]. Furthermore, It has been found in number of cancer models that tumor inflammatory microenvironment constitutes complement activated fragments C3, C4, and C5, Clq, and MAC [ 12 ], high levels of IL-6 [ 25 ] and TGF-β [ 26 ]. IL-6 has been shown to assist tumor progression though apoptosis inhibition, angiogenesis stimulation [ 27 ].…”

Cancer and the Complement Cascade

“…Other evidence indicates that complement proteins induce production of transforming growth factor-β (TGF-β; refs. [73][74][75][76], an especially compelling finding given its complex relationship to neoplastic progression (77). TGF-β has the potential to both inhibit and enhance neoplasia (74,75,77), suggesting that its effects may depend on more specific tumor characteristics such as stage and type (3).…”