Local extravascular pool of C3 is a determinant of postischemic acute renal failure

Farrar, Conrad A.; Zhou, Wuding; Lin, Tao; Sacks, Steven H.

doi:10.1096/fj.05-4747com

Cited by 181 publications

(183 citation statements)

References 45 publications

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“…25,33 C3 of proximal tubule cell origin is a crucial mediator of injury in experimental acute allograft rejection and after renal ischemia and reperfusion. 23,34 Its expression was enhanced in both human and experimental proteinuric nephropathies. 35 Moreover, exposing cultured proximal tubular cells to serum proteins at the apical surface enhanced C3 mRNA expression 36 and secretion.…”

Section: Discussionmentioning

confidence: 99%

Complement-Mediated Dysfunction of Glomerular Filtration Barrier Accelerates Progressive Renal Injury

Abbate

Zoja

Corna

et al. 2008

Journal of the American Society of Nephrology

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Intrarenal complement activation leads to chronic tubulointerstitial injury in animal models of proteinuric nephropathies, making this process a potential target for therapy. This study investigated whether a C3-mediated pathway promotes renal injury in the protein overload model and whether the abnormal exposure of proximal tubular cells to filtered complement could trigger the resulting inflammatory response. Mice with C3 deficiency were protected to a significant degree against the protein overload-induced interstitial inflammatory response and tissue damage, and they had less severe podocyte injury and less proteinuria. When the same injury was induced in wild-type (WT) mice, antiproteinuric treatment with the angiotensin-converting enzyme inhibitor lisinopril reduced the amount of plasma protein filtered, decreased the accumulation of C3 by proximal tubular cells, and protected against interstitial inflammation and damage. For determination of the injurious role of plasma-derived C3, as opposed to tubular cell-derived C3, C3-deficient kidneys were transplanted into WT mice. Protein overload led to the development of glomerular injury, accumulation of C3 in podocytes and proximal tubules, and tubulointerstitial changes. Conversely, when WT kidneys were transplanted into C3-deficient mice, protein overload led to a more mild disease and abnormal C3 deposition was not observed. These data suggest that the presence of C3 increases the glomerular filtration barrier's susceptibility to injury, ultrafiltered C3 contributes more to tubulointerstitial damage induced by protein overload than locally synthesized C3, and local C3 synthesis is irrelevant to the development of proteinuria. It is speculated that therapies targeting complement combined with interventions to minimize proteinuria would more effectively prevent the progression of renal disease.

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Section: Discussionmentioning

confidence: 99%

Complement-Mediated Dysfunction of Glomerular Filtration Barrier Accelerates Progressive Renal Injury

Abbate

Zoja

Corna

et al. 2008

Journal of the American Society of Nephrology

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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] . …”

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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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“…Plasma-derived C 3 (molecular weight 180kd) is likely to reflect more loss of glomerular permselectivity and to enhance cell dysfunction in the presence of abnormally filtered plasma proteins. Renal tubular cells also synthesize C 3 and other complement factors in ways that may have critical importance in disease, as found in experimental renal transplant rejection and post ischemic acute renal failure (Pratt et al,2002;Farrar et al, 2006). Therefore both excess ultrafiltration and proximal tubular cell synthesis of complement could underlie complement -mediated injury in chronic proteinuric renal disease.…”

Section: Key Role For the Intra-renal Activation Of Complementmentioning

confidence: 99%