Renal Expression of the C3a Receptor and Functional Responses of Primary Human Proximal Tubular Epithelial Cells

Braun, Michael C.; Reins, Rose Y.; Li, Tong Bin; Hollmann, Travis J.; Dutta, Ranjan; Rick, W.; Teng, Ba Bie; Ke, Baozhen

doi:10.4049/jimmunol.173.6.4190

Cited by 71 publications

(53 citation statements)

References 48 publications

(41 reference statements)

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Section: Discussionmentioning

confidence: 99%

“…Both are located on proximal tubular epithelial cells, [21][22][23] while in the glomerulus, C3a and C5a receptors appear specific to podocytes and mesangial cells, respectively. 16,21,24,25 Systemic administration of lipopolysaccharide can markedly increase mesangial C5aR expression, which is dependent on urokinase receptor activation. 26 Early in the course of murine lupus nephritis, both C3a and C5a receptor are significantly upregulated, while later in the course of disease, their specific inhibition 16,19 or deletion 27 lessened glomerular disease manifestations.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Decay-accelerating factor but not CD59 limits experimental immune-complex glomerulonephritis

Bao

Haas

Minto

et al. 2007

Laboratory Investigation

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The complex balance between the pro-activating and regulatory influences of the complement system can affect the pathogenesis of immune complex-mediated glomerulonephritis (ICGN). Key complement regulatory proteins include decay accelerating factor (DAF) and CD59, which inhibit C3 activation and C5b-9 generation, respectively. Both are glycosylphosphatidylinositol-linked cell membrane proteins, which are widely distributed in humans and mice. Chronic serum sickness induced by daily immunization with horse spleen apoferritin over 6 weeks was used to induce ICGN in DAF-, CD59-and DAF/CD59-deficient mice, with wild-type littermate mice serving as controls. Both DAF and DAF/CD59-deficient mice had an increased incidence of GN relative to wild-type controls associated with significantly increased glomerular C3 deposition. Disease expression in CD59-deficient mice was no different than wild-type controls. DAF-and DAF/CD59-deficient mice also had increased monocyte chemoattractant protein-1 mRNA expression and glomerular infiltration with CD45 þ leukocytes. Our findings suggest that activation of C3 is strongly associated with experimental ICGN while downstream formation of C5b-9 is of lesser pathogenic importance in this model.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Decay-accelerating factor but not CD59 limits experimental immune-complex glomerulonephritis

Bao

Haas

Minto

et al. 2007

Laboratory Investigation

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“…26 Alternative pathway complement activation through C3 convertase leads to C5b-9 (MAC) binding on tubular cell surface 12 and causes tubular cell dysfunction via reactive oxygen species and cytokines. 26 A monocyte-activating amidated form of C3, 12 C3a, 27,28 and C5 29 can also be pathogenic.…”

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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“…Renal epithelial can also respond to the anaphylatoxins, expressing both C3a receptor (C3aR) [74] and C5aR [75] . Tubular cells exposed to C3a, possibly synthesised from the tubular cells themselves [76] , increase collagen synthesis [74] and adopt a more mesenchymal phenotype [39] . Similar effects can be seen in tubular epithelial cells exposed to C5a.…”

Section: Effect Of Complement On Renal Cell Functionmentioning

confidence: 99%

“…Complement can also induce expression of major histocompatibility antigens on tubular cells, allowing these cells to drive T cell proliferative responses, potentially augmenting allo and autoimmunity [73] . Renal epithelial can also respond to the anaphylatoxins, expressing both C3a receptor (C3aR) [74] and C5aR [75] . Tubular cells exposed to C3a, possibly synthesised from the tubular cells themselves [76] , increase collagen synthesis [74] and adopt a more mesenchymal phenotype [39] .…”

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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Renal Expression of the C3a Receptor and Functional Responses of Primary Human Proximal Tubular Epithelial Cells

Cited by 71 publications

References 48 publications

Decay-accelerating factor but not CD59 limits experimental immune-complex glomerulonephritis

Decay-accelerating factor but not CD59 limits experimental immune-complex glomerulonephritis

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

Complement activation in progressive renal disease

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