Complement Activation Contributes to Both Glomerular and Tubulointerstitial Damage in Adriamycin Nephropathy in Mice

Abstract

Adriamycin nephropathy is a model of focal segmental glomerulosclerosis, characterized by proteinuria and progressive glomerulosclerosis and tubulointerstitial damage. In this study, we examined the role of complement in the etiology of adriamycin nephropathy in mice. We used mice deficient in C1q, factor D, C3, and CD59, and compared them with strain-matched controls. C3 deposition occurred in the glomeruli of wild-type mice as early as 48 h following a single i.v. injection of adriamycin. C3-deficient mice developed significantly less proteinuria and less podocyte injury at day 3 postadriamycin than controls, suggesting that complement is important in mediating the early podocyte injury. At later time points, C3-deficient mice were protected from glomerulosclerosis, tubulointerstitial injury, and renal dysfunction. Factor D-deficient mice were also protected from renal disease, confirming the importance of alternative pathway activation in this model. In contrast, C1q-deficient mice developed similar disease to controls, indicating that the complement cascade was not activated via the classical pathway. CD59-deficient mice, which lack adequate control of C5b-9 formation, developed significantly worse histological and functional markers of renal disease than controls. Interestingly, although more C9 deposited in glomeruli of CD59-deficient mice than controls, in neither group was tubulointerstitial C9 staining apparent. We have demonstrated for the first time that alternative pathway activation of complement plays an important role in mediating the initial glomerular damage in this in vivo model of focal segmental glomerulosclerosis. Lack of CD59, which regulates the membrane attack complex, led to greater glomerular and tubulointerstitial injury.

Renal Monoclonal Immunoglobulin Deposition Disease

“…These differences may relate to the ability of the heavy chain to activate complement, a property that light chains lack. Complement activation, which is typically detectable by immunofluorescence in these cases, may have direct effects on mesangial cells and podocytes to promote matrix production and greater proteinuria (19,20). Patient outcome, however, was not statistically different between HCDD and LCDD.…”

Clinical Significance of IgM and C3 Glomerular Deposition in Primary Focal Segmental Glomerulosclerosis

“…Dual staining of FSGS kidney tissue showed colocalization of IgM and C3d when they were both present (3). In an adriamycin-induced FSGS animal model, complement activation was shown in both glomeruli and tubule, which could lead to tissue damage (28,29). Recently, IgM was shown as the activator for complements and to contribute to kidney injury progression (3,4).…”

IgM Contributes to Glomerular Injury in FSGS

“…IgM is a classical pathway activator, but we and others previously demonstrated a role for alternative pathway amplification in this model. 28,36 It is possible, therefore, that glomerular injury simultaneously increases classical pathway activation by natural IgM, which binds to injury associated epitopes, while also decreasing the ability of complement regulatory proteins within the glomerulus to control amplification of complement activation through the alternative pathway. The primary treatments for idiopathic FSGS are immunosuppressive drugs, yet it has remained uncertain whether FSGS is an immune-mediated disease.…”

“…FSGS is a very heterogeneous disease, however, both clinically and morphologically. 34,35 Although B cell depletion and complement deficiency contribute to the early development of albuminuria in the adriamycin model, 28,36 Ig-and complement-mediated injury may be secondary phenomena that occur after a primary renal insult. We have observed glomerular IgM deposition after ischemic and chemical injury of the kidneys, 25 suggesting that diverse insults may generate glomerular neoepitopes.…”