Is there a role for locally produced complement in renal disease?

Mohamed R. Daha and Cees van Kooten

Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands

Introduction

It has been shown that complement is a major mediator system in the pathogenesis of several, especially immune-complex-mediated, kidney diseases. The major site of synthesis of complement components is the liver; however, several studies indicate that extrahepatic production of complement components can be substantial. For the first subcomponent of complement C1q, it is believed that the production occurs primarily at extrahepatic sites, most probably by macrophage-like cells. Other cells that have been implicated in complement production are endothelial cells, epithelial cells, many kidney-, skin-, brain- and synovial-cells [1]. One of the main questions is: What the function is of locally produced complement proteins?

Expression of complement in the kidney

Depositions of immunoglobulins together with complement components are frequently encountered in glomeruli of diseased kidneys. The question is, however, whether these complement proteins are derived from the circulation and thus mainly synthesized by hepatocytes or whether these complement components are produced locally by intrinsic renal cells. Local synthesis of complement components in the kidney was found in two murine models of immune-complex disease [2,3] and an increased mRNA expression for several complement genes was found in MRL lpr/lpr inbred mice which spontaneously develop SLE-like disease. Messenger RNA isolated from the renal cortex of these mice exhibited a clear increase in C3, C4, and C2 mRNA in nephritic kidneys.

For factor B two mRNA transcripts, differing in size, were elevated in nephritic kidneys, suggesting a possible contribution of infiltrating cells in the local production of complement, in addition to intrinsic production. In the (NZBxNZW) F1 hybrid with naturally occurring glomerulonephritis it was also observed that C4, C3, and factor B mRNA expression was raised in the kidney. The hepatic expression of complement genes in these two murine models of glomerulonephritis was not increased after the onset of nephritis. In human kidneys, Feucht et al. [4] were the first to demonstrate expression of C4 mRNA in amounts comparable to those of the liver. The C4 mRNA expression in these kidneys was detected in the interstitium, not in the glomerular part of the cortex. Factor B was expressed only in low amounts in the kidney as compared to the liver, while C2 message could not be detected in the normal human kidney. These findings were supported by in situ hybridization, i.e. the message of C4 was located in the tubules of normal kidneys, while mRNA expression of C4, C3 and factor B was present in tubules of diseased kidneys [5,6].

More evidence that increased expression of complement genes occurs during local inflammation in the kidney was obtained from a study in which RT–PCR analysis was performed on mRNA isolated from normal and diseased kidney tissue. Sacks et al. [7] investigated the C3 gene expression in kidney biopsies from patients with immune complex glomerulonephritis, cell-mediated interstitial nephritis, or non-immune glomerular injury. In the biopsies of the two first groups of patients a significant increase in C3 expression was found, while this was not obvious in the latter group. In another study, C2 mRNA expression was detected in the biopsies of patients with cellular rejection and cyclosporin A nephrotoxicity [8]. However, it was difficult to ascertain whether intrinsic renal cells or infiltrating cells were the local source of complement in these kidneys. To overcome this problem, Andrews et al. [9] investigated donor-specific C3 mRNA in kidneys of patients with a renal graft. It was possible to perform these studies because the patients were mismatched in their C3 allotypes. Both by RT–PCR and by staining with specific antibodies it was possible to discriminate between the C3F and C3S allotypes. Donor-specific C3 mRNA expression was observed in six of the nine case studies and by staining of frozen sections of renal cortex material predominantly tubular epithelial cells but also glomerular cells were identified as producers of C3. A summary of these findings is presented in Table 1Go.


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Table 1. Detection of C3 mRNA in renal disease

 
In the mean time a large number of studies have shown that various renal cells are able to produce several complement components (Table 2Go) and that most of these components are subject to regulation by growth factors and cytokines [1018]. Glomerular mesangial cells produce C3 and C4, while renal tubular epithelial cells produce a host of complement components. Little is known about the production of complement by human glomerular endothelial cells; however, the production of almost all complement components has been documented for human umbilical vein endothelial cells.


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Table 2. Renal cells and infiltrating cells involved in the production of complement components in the kidney

 
While most emphasis regarding the production of complement components has been on the early components of both the classical and alternative pathways of complement activation, neither the late components of complement such as C5–C9, nor the components of the recently described mannose binding lectin pathway have received proper attention. On the other hand, a direct effect of activation fragments such as C3a and C5a or of the C5b–C9 complex on renal cells indicate that complement activation may have a modulating role in activation of local renal cells [19].

Is there a role for locally produced complement in the kidney?

Several studies in experimental models have examined a possible relationship between local complement production and tissue injury. A relationship was found between the progressive increase in synthesis of C2, C4, C3 and factor B in nephritic kidneys that coincided with development of renal injury [3,4]. Also, studies in the passive Heymann nephritis model of membranous glomerulonephritis demonstrated a parallel relationship between an increase in renal epithelial expression of C4 and the development of proteinuria [20]. These studies do not establish a causal role for the contribution of locally produced complement, because a significant contribution by systematically produced complement could not be excluded. Attempts to obtain insight in contribution to local inflammation by locally produced C6 in the Thy.1 model of nephritis were unsuccessful because no C6 production was detectable by mesangial cells in the rat [21]. More recently it was demonstrated that in the Thy.1 model C5b–C9 membrane attack complex may provide a direct signal to mesangial cells in vivo and induce early apoptosis of mesangial cells [22]. This observation combined with the observation that local synthesis of C3, factor B, factor H, C2, and C4 already occurs in the prenatal phase of development of the kidney [23], may suggest that complement could play a role during the development of the kidney.

A strong association has been found for the occurrence of autoimmune disease, especially immune-complex-mediated injury, in conjunction with a primary or a secondary deficiency of C1q [24]. Almost all individuals with C1q deficiency develop autoimmune disease and renal inflammation. Also a strong correlation was found between the occurrence of anti C1q antibodies and renal disease in patients with systemic lupus erythematosus. One of the striking features found in mice with a homozygous C1q deficiency is glomerulonephritis associated with multiple apoptotic bodies [25]. It is thought that apoptotic cells under normal physiological conditions are recognized by C1q and presented to phagocytic cells such as macrophages, which then clear these cells from the kidney and prevent inflammation. Since C1q is produced primarily by macrophages it is possible that locally produced C1q is instrumental in clearance of apoptotic cells from the micro-environment of the kidney.

However, to prove conclusively that local production of complement contributes to local homeostasis of regulation or remodelling, either during development or following injury, one has to await studies in complement deficient animals and/or transplantation of kidneys from complement-sufficient individuals or animals into complement-deficient subjects. Further possibilities are to repopulate renal cells of complement-deficient animals by complement-sufficient cells. In addition, reintroduction of missing components under the control of tissue-specific promoters may help to establish a role of particular components in renal disease.

Concluding remarks

Systemic levels of complement are mainly determined by hepatic production and fulfil important roles in immune defence and immune complex processing. Because of the large size of complement components, one can imagine that penetration of plasma complement into tissues is limited. Therefore it is possible that in many tissues locally produced complement may compensate for this relative lack of plasma complement. The local presence of various growth factors and cytokines may enhance local synthesis of complement and provide a means for enhanced defence against local infections and/or modulating of injured tissue.

Notes

Correspondence and offprint requests to: M. R. Daha, Department of Nephrology, University Medical Center, Building 1, C3P, PO Box 9600, 2300 RC Leiden, The Netherlands. Back

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