Novel insights in localization and expression levels of C5aR and C5L2 under native and post-transplant conditions in the kidney

Werkhoven, Maaike B. van; Damman, Jeffrey; Daha, Mohamed R.; Krikke, Christina; Goor, Harry van; Son, Willem J. van; Hillebrands, Jan-Luuk; Dijk, Marcory C. R. F. van; Seelen, Marc A.

doi:10.1016/j.molimm.2012.08.013

Cited by 26 publications

(21 citation statements)

References 38 publications

(50 reference statements)

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“…14,15,17,18 Complement proteins may be filtered through an injured glomerulus and basement membrane 65 or may propagate terminal complement activation locally at the proximal tubule, 66 contributing directly to tubular inflammation (C3a, C5a) and cell death (C5b-9). 48,49 A role for C5 activation in tubular injury is also supported by the finding that C5a receptors in the nephron are concentrated in the proximal tubule 67,68 and that urinary excretion of C5b-9 correlates with active disease in severe preeclampsia. 20 Considering our finding that terminal complement activation (ie, C5a and C5b-9) in severe preeclampsia is most closely associated with KIM-1, a specific marker of proximal tubule injury, targeted therapeutics to reduce complement activation or proximal tubule injury in severe preeclampsia may be useful in prevention or treatment of disease.…”

Section: Discussionmentioning

confidence: 90%

Complement Activation and Kidney Injury Molecule-1–Associated Proximal Tubule Injury in Severe Preeclampsia

et al. 2014

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We enrolled 25 cases with severe preeclampsia, 25 controls with chronic hypertension, and 25 healthy controls without hypertension from a cohort of women receiving care at Brigham and Women's Hospital from March 2012 through March 2013. Institutional review board approval was obtained through the Partners Human Research Committee, and subjects gave informed consent. All procedures followed were in accordance with institutional guidelines. Methods Abstract-Kidney injury with proteinuria is a characteristic feature of preeclampsia, yet the nature of injury in specific regions of the nephron is incompletely understood. Our study aimed to use existing urinary biomarkers to describe the pattern of kidney injury and proteinuria in pregnancies affected by severe preeclampsia. We performed a case-control study of pregnant women from Brigham and Women's Hospital from 2012 to 2013. We matched cases of severe preeclampsia (n=25) 1:1 by parity and gestational age to 2 control groups with and without chronic hypertension. Urinary levels of kidney injury molecule-1 and complement components (C3a, C5a, and C5b-9) were measured by enzyme-linked immunosorbent assay, and other markers (albumin, β2 microglobulin, cystatin C, epithelial growth factor, neutrophil gelatinase-associated lipocalin, osteopontin, and uromodulin) were measured simultaneously with a multiplex electrochemiluminescence assay. Median values between groups were compared with the Wilcoxon signed-rank test and correlations with Spearman correlation coefficient. Analysis of urinary markers revealed higher excretion of albumin and kidney injury molecule-1 and lower excretion of neutrophil gelatinase-associated lipocalin and epithelial growth factor in severe preeclampsia compared with chronic hypertension and healthy controls. Among subjects with severe preeclampsia, urinary excretion of complement activation products correlated most closely with kidney injury molecule-1, a specific marker of proximal tubule injury (C5a: r=0.60; P=0.001; and C5b-9: r=0.75; P<0.0001). Taken together, we describe a pattern of kidney injury in severe preeclampsia that is characterized by glomerular impairment and complement-mediated inflammation and injury, possibly localized to the proximal tubule in

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Section: Discussionmentioning

confidence: 90%

Complement Activation and Kidney Injury Molecule-1–Associated Proximal Tubule Injury in Severe Preeclampsia

et al. 2014

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“…However, C5a has high affinity for its receptors and is rapidly cleared from circulation. Furthermore, distinct C5a receptors in the kidney may be expressed in the proximal tubule or thick ascending limb of Henle loop (C5aR) or the distal convoluting tubule (C5L2), [40][41][42] which may limit the usefulness of urinary C5a as a biomarker of disease activity. C5b-9 seems to be a more reliable urinary marker for various renal diseases.…”

Section: Discussionmentioning

confidence: 99%

Urinary Excretion of C5b-9 in Severe Preeclampsia

et al. 2013

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Abstract-The complement cascade is activated in normal pregnancy, and excessive complement activation propagates the systemic inflammatory response in severe preeclampsia. Consequently, biomarkers of complement dysregulation may be useful for prediction or treatment of disease. Because renal damage with proteinuria is a characteristic pathological feature of preeclampsia, we hypothesized that complement markers in urine, rather than plasma, could better reflect complement dysregulation in disease. 0001).Urinary excretion of C5b-9 was detected in 96% of cases with severe preeclampsia, 12% of controls with chronic hypertension, and 8% of healthy controls. Cases were also notable for significantly greater urinary excretion of C3a and C5a. Plasma levels of C5a and C5b-9, but not C3a, were increased in the cases with severe preeclampsia compared with healthy controls; however, they did not distinguish preeclampsia from chronic hypertension, supporting our hypothesis that complement markers in urine, rather than plasma, better reflect complement dysregulation. Complement inhibition is an intriguing treatment option for patients with severe preeclampsia. (Hypertension. 2013;62:1040-1045.)

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“…Its expression on T cells is still controversial (11,12). On nonimmune cells, C5aR1 was found on tubular, endothelial, and smooth muscle cells (7,28). The complement cascade is well appreciated as an important driver of various kidney diseases (19).…”

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confidence: 99%

The complement receptor C5aR1 contributes to renal damage but protects the heart in angiotensin II-induced hypertension

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Rosendahl

Czesla

et al. 2016

American Journal of Physiology-Renal Physiology

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Adaptive and innate immune responses contribute to hypertension and hypertensive end-organ damage. Here, we determined the role of anaphylatoxin C5a, a major inflammatory effector of the innate immune system that is generated in response to complement activation, in hypertensive end-organ damage. For this purpose, we assessed the phenotype of C5a receptor 1 (C5aR1)-deficient mice in ANG II-induced renal and cardiac injury. Expression of C5aR1 on infiltrating and resident renal as well as cardiac cells was determined using a green fluorescent protein (GFP)-C5aR1 reporter knockin mouse. Flow cytometric analysis of leukocytes isolated from the kidney of GFP-C5aR1 reporter mice showed that 28% of CD45-positive cells expressed C5aR1. Dendritic cells were identified as the major C5aR1-expressing population (88.5%) followed by macrophages and neutrophils. Using confocal microscopy, we detected C5aR1 in the kidney mainly on infiltrating cells. In the heart, only infiltrating cells stained C5aR1 positive. To evaluate the role of C5aR1 deficiency in hypertensive injury, an aggravated model of hypertension was used. Unilateral nephrectomy was performed followed by infusion of ANG II (1.5 ng·g(-1)·min(-1)) and salt in wild-type (n = 34) and C5aR1-deficient mice (n = 32). C5aR1-deficient mice exhibited less renal injury, as evidenced by significantly reduced albuminuria. In contrast, cardiac injury was accelerated with significantly increased cardiac fibrosis and heart weight in C5aR1-deficient mice after ANG II infusion. No effect was found on blood pressure. In summary, the C5a:C5aR1 axis drives end-organ damage in the kidney but protects from the development of cardiac fibrosis and hypertrophy in experimental ANG II-induced hypertension.

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Novel insights in localization and expression levels of C5aR and C5L2 under native and post-transplant conditions in the kidney

Cited by 26 publications

References 38 publications

Complement Activation and Kidney Injury Molecule-1–Associated Proximal Tubule Injury in Severe Preeclampsia

Complement Activation and Kidney Injury Molecule-1–Associated Proximal Tubule Injury in Severe Preeclampsia

Urinary Excretion of C5b-9 in Severe Preeclampsia

The complement receptor C5aR1 contributes to renal damage but protects the heart in angiotensin II-induced hypertension

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