Regulation of Complement Activation by Heme Oxygenase-1 (HO-1) in Kidney Injury

Abstract

Heme oxygenase is a cytoprotective enzyme with strong antioxidant and anti-apoptotic properties. Its cytoprotective role is mainly attributed to its enzymatic activity, which involves the degradation of heme to biliverdin with simultaneous release of carbon monoxide (CO). Recent studies uncovered a new cytoprotective role for heme oxygenase-1 (HO-1) by identifying a regulatory role on the complement control protein decay-accelerating factor. This is a key complement regulatory protein preventing dysregulation or overactivation of complement cascades that can cause kidney injury. Cell-specific targeting of HO-1 induction may, therefore, be a novel approach to attenuate complement-dependent forms of kidney disease.

Keywords: complement; heme; heme oxygenase-1 (HO-1); kidney injury.

Figure 1

Schematic representation of the glomerulus. The glomerulus is a tuft of capillaries located within Bowman’s capsule. It is composed of an afferent arteriole, supplying the glomerular capillaries, and an efferent arteriole, into which they drain. Each glomerulus consists of three different cell types: mesangial cells, endothelial cells, and podocytes. Mesangial cells and the mesangial matrix provide structural support for the glomerular capillaries, lined by specialized endothelial cells, which are fenestrated. On the urinary side of the glomerular basement membrane are located glomerular epithelial cells, podocytes, which have long foot processes called pedicels that wrap around the glomerular capillaries. In glomerular disease, complement deposition can be found in all three cell types. Podocytes are the most vulnerable to complement-mediated injury because they are terminally differentiated and their ability to upregulate cytoprotective systems, such as HO-1, is limited.

Figure 2

Exposure of the glomerular microvasculature to various heme oxygenase-1 (HO-1) inducers. Numerous HO-1 inducers, including heme, hydrogen peroxide (H₂O₂), and peroxynitrite (ONOO⁻), are present in the glomerular milieu under conditions of glomerular injury, which may activate HO-1. Once activated, the cytoprotective enzyme degrades heme and releases Fe²⁺ and carbon monoxide (CO). Biliverdin is then converted to bilirubin in the presence of biliverdin reductase and NADPH. The HO-1 reaction products (CO, biliverdin, bilirubin) have well-known antioxidant and antiapoptotic properties and potentially mediate the activation or inhibition of various cellular pathways or may act as immunomodulators.

Figure 3

Complement cascade regulation by the heme–HO-1 axis. Central to the activation of complement is the cleavage of circulating C3 to form C3a and C3b. This occurs spontaneously at a low rate in circulation but can be accelerated by: (i) the classical pathway, in which antibodies bound to antigen recruit the C1 complex which, via the activation of circulating C4 and C2, increases the rate of C3 cleavage at the antibody-coated surface; (ii) the alternative pathway (AP), in which C3b binds to circulating factor Bb to form the C3bBb complex that is stabilized by the presence of a biological surface and provides a mechanism for positive feedback, allowing massive C3 activation. Uncontrolled C3 activation is prevented by cell surface regulators, including decay-accelerating factor (DAF, CD55) and membrane co-factor protein (MCP, CD46). C3b generation promotes the cleavage of circulating C5 to form C5a and C5b. C5b generation activates the terminal pathway, in which C6–C9 are recruited to form the membrane attack complex (C5b-9), a pore-like structure causing the lysis of targeted cells. Heme inhibits the classical complement pathway by directly binding to C1q, thus causing changes to IgG binding. On the other hand, heme promotes the activation of the alternative complement pathway and increases C3 deposits. HO-1 regulates the expression of DAF which acts by inhibiting uncontrolled activation of the complement cascade at both the C3 and the C5 level. Therefore, the induction of HO-1 may act as a complement inhibitor, whereas HO-1 depletion may result in the overactivation or unbalanced activation of the complement cascade.