Synthesis of complement protein C3 in the kidney is an important mediator of local tissue injury

Sheerin, Neil; Risley, Paul; Abe, Katsushige; Tang, Ziyong; Wong, Wilson; Lin, Tao; Sacks, Steven H.

doi:10.1096/fj.07-8719com

Cited by 79 publications

(64 citation statements)

References 37 publications

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“…It can be hypothesized that complement overexpression in stable grafts is associated with subclinical but in the long term deleterious complement activation, contributing to chronic histologic damage, graft dysfunction, and ultimately graft loss. This is supported by previous animal studies [35][36][37] and by the recent observation that the complement C3 allotype of the donor was associated with graft survival as a result of "chronic allograft nephropathy, " interstitial fibrosis, and tubular atrophy but not with differences in the prevalence or severity of rejection episodes, 16 which reinforces this hypothesis also in a human setting. The overexpression of genes involved in immunity and fibrosis in posttransplantation samples included in this study fits well with this hypothesis.…”

Section: Discussionsupporting

confidence: 81%

Expression of Complement Components Differs Between Kidney Allografts from Living and Deceased Donors

Naesens¹,

Li²,

Ying³

et al. 2009

Journal of the American Society of Nephrology

122

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A disparity remains between graft survival of renal allografts from deceased donors and from living donors. A better understanding of the molecular mechanisms that underlie this disparity may allow the development of targeted therapies to enhance graft survival. Here, we used microarrays to examine whole genome expression profiles using tissue from 53 human renal allograft protocol biopsies obtained both at implantation and after transplantation. The gene expression profiles of living-donor kidneys and pristine deceased-donor kidneys (normal histology, young age) were significantly different before reperfusion at implantation. Deceased-donor kidneys exhibited a significant increase in renal expression of complement genes; posttransplantation biopsies from well-functioning, nonrejecting kidneys, regardless of donor source, also demonstrated a significant increase in complement expression. Peritransplantation phenomena, such as donor death and possibly cold ischemia time, contributed to differences in complement pathway gene expression. In addition, complement gene expression at the time of implantation was associated with both early and late graft function. These data suggest that complementmodulating therapy may improve graft outcomes in renal transplantation. The persisting graft survival difference between living-and deceased-donor kidneys for renal transplantation 1,2 suggests that a significant potential to improve graft survival further lies in new approaches to overcome the deleterious effects of often inevitable longer cold ischemia times 3 and brain death. 4 Apart from further refining storage solutions and machine perfusion techniques, targeted therapy and modulation of specific pathways before organ retrieval, during cold storage or after implantation, could have beneficial effects and improve the outcome of deceased-donor kidney transplantation.To identify these specific pathways underlying the difference between pristine (normal histology, young donor age) deceased-and living-donor kidneys, we undertook this microarray study comparing implantation and posttransplantation protocol biopsies without rejection, in both deceased-and living-donor recipients. Previous studies using gene expression microarray experiments on implantation biopsies have demonstrated expression profile differences between living-and marginal deceaseddonor kidneys, 5-7 have not always been validated in independent data sets, 5,6 and did not always provide in-depth analyses of the pathways involved. [5][6][7] In

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Section: Discussionsupporting

confidence: 81%

Expression of Complement Components Differs Between Kidney Allografts from Living and Deceased Donors

Naesens¹,

Li²,

Ying³

et al. 2009

Journal of the American Society of Nephrology

122

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“…The functional and structural changes of chronic renal allograft failure share similarities with those observed in other forms of chronic progressive kidney disease, in which decline of functioning nephron mass has been considered the key event (107). Emerging evidence suggests that intragraft complement activation contributes to this progressive kidney injury (108). C3 is implicated in the activation of the renin-angiotensin system and the epithelial-to-mesenchymal transition (109,110).…”

Section: Kidney-derived Complement and Diseasementioning

confidence: 90%

Molecules Great and Small

Mathern

Heeger

2015

Clinical Journal of the American Society of Nephrology

242

192

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The complement cascade, traditionally considered an effector arm of innate immunity required for host defense against pathogens, is now recognized as a crucial pathogenic mediator of various kidney diseases. Complement components produced by the liver and circulating in the plasma undergo activation through the classical and/or mannose-binding lectin pathways to mediate anti-HLA antibody-initiated kidney transplant rejection and autoantibody-initiated GN, the latter including membranous glomerulopathy, antiglomerular basement membrane disease, and lupus nephritis. Inherited and/or acquired abnormalities of complement regulators, which requisitely limit restraint on alternative pathway complement activation, contribute to the pathogenesis of the C3 nephropathies and atypical hemolytic uremic syndrome. Increasing evidence links complement produced by endothelial cells and/or tubular cells to the pathogenesis of kidney ischemia-reperfusion injury and progressive kidney fibrosis. Data emerging since the mid-2000s additionally show that immune cells, including T cells and antigen-presenting cells, produce alternative pathway complement components during cognate interactions. The subsequent local complement activation yields production of the anaphylatoxins C3a and C5a, which bind to their respective receptors (C3aR and C5aR) on both partners to augment effector T-cell proliferation and survival, while simultaneously inhibiting regulatory T-cell induction and function. This immune cell-derived complement enhances pathogenic alloreactive T-cell immunity that results in transplant rejection and likely contributes to the pathogenesis of other T cell-mediated kidney diseases. C5a/C5aR ligations on neutrophils have additionally been shown to contribute to vascular inflammation in models of ANCA-mediated renal vasculitis. New translational immunology efforts along with the development of pharmacologic agents that block human complement components and receptors now permit testing of the intriguing concept that targeting complement in patients with an assortment of kidney diseases has the potential to abrogate disease progression and improve patient health.

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“…A strategy of renal syngenic or allogeneic transplantation in knockout mice can create a mouse which has a deficiency only in local complement synthesis. Application of this strategy has demonstrated a role for local C3 synthesis in transplant rejection [66] , ischaemic reperfusion injury [92] and tubulointerstitial injury in proteinuric disease [93] . …”

mentioning

confidence: 99%

Complement activation in progressive renal disease

Fearn

Sheerin

2015

WJN

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ritis, thrombotic microangiopathies and transplant reje ction. In this review we discuss current evidence that complement activation contributes to progression of CKD, how complement could cause renal inflammation and whether complement inhibition would slow progression of renal disease. Core tip: Complement activation occurs in progressive chronic kidney disease and may contribute to the chronic inflammation that is characteristically found in the kidney. It is therefore possible that inhibiting complement activation would reduce inflammation, lead to reduced fibrosis and preservation of renal function. INTRODUCTIONChronic kidney disease (CKD) is recognised worldwide as a major public health problem [1] . In 2007 the United Kingdom age-standardised prevalence of CKD stages 3-5 was 8.5% (10.6% in females and 5.8% in males) [2] and similar prevalences have been described in other countries. In 2012 in the United Kingdom, the number of new patients requiring renal replacement therapy was 6891, equating to 108 patients per million population, with diabetes and glomerulonephritis being the two most common diagnoses in incident dialysis patients. Although not all patients with CKD will progress to renal failure, all stages of CKD are associated with increased AbstractChronic kidney disease (CKD) is common and the cause of significant morbidity and mortality. The replacement of functioning nephrons by fibrosis is characteristic of progressive disease. The pathways that lead to fibrosis are not fully understood, although chronic nonresolving inflammation in the kidney is likely to drive the fibrotic response that occurs. In patients with progressive CKD there is histological evidence of inflammation in the interstitium and strategies that reduce inflammation reduce renal injury in preclinical models of CKD. The complement system is an integral part of the innate immune system but also augments adaptive immune responses. Complement activation is known to occur in many diverse renal diseases, including glomeruloneph morbidity and mortality [1] . Tubulointerstitial inflammation and fibrosis is a major factor in the progressive loss of renal function in most kidney diseases [3] . The process is complex due to the number of interacting pathways which ultimately result in the replacement of functioning nephrons with scar tissue. Cellular stress and injury induces an inflammatory and pro-fibrogenic response involving growth factors [4][5][6] and pro-inflammatory cytokines as well as activation of the renin-angiotensin system. This leads to a chronic inflammatory cell infiltrate, increasing numbers of activated fibroblasts (myofibroblasts) and excessive matrix deposition. There is evidence from preclinical models that the immune system is important in the development of renal fibrosis [7,8] . A component of the innate immune system that may be important in driving renal inflammation is the complement system, which can directly affect cell function and also influence the adaptive immune response. REVIEW COMPLEMENT SYSTEMTh...

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Synthesis of complement protein C3 in the kidney is an important mediator of local tissue injury

Cited by 79 publications

References 37 publications

Expression of Complement Components Differs Between Kidney Allografts from Living and Deceased Donors

Expression of Complement Components Differs Between Kidney Allografts from Living and Deceased Donors

Molecules Great and Small

Complement activation in progressive renal disease

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