Role of Intracellular complement activation in kidney fibrosis

2021 ◽  
Author(s):  
Didier Portilla ◽  
Sandhya Xavier
Keyword(s):  
Complement Activation ◽  
Kidney Fibrosis

scholarly journals Pericytes and immune cells contribute to complement activation in tubulointerstitial fibrosis

2017 ◽  
Vol 312 (3) ◽  
pp. F516-F532 ◽  
Author(s):  
Sandhya Xavier ◽  
Ranjit K. Sahu ◽  
Susan G. Landes ◽  
Jing Yu ◽  
Ronald P. Taylor ◽  
...  
Keyword(s):  
Complement Activation ◽  
Kidney Tissue ◽  
Flow Cytometry Analysis ◽  
Pathogenic Role ◽  
Local Synthesis ◽  
Kidney Fibrosis ◽  
Extracellular Matrix Components ◽  
Complement Gene ◽  
Matrix Components

We have examined the pathogenic role of increased complement expression and activation during kidney fibrosis. Here, we show that PDGFRβ-positive pericytes isolated from mice subjected to obstructive or folic acid injury secrete C1q. This was associated with increased production of proinflammatory cytokines, extracellular matrix components, collagens, and increased Wnt3a-mediated activation of Wnt/β-catenin signaling, which are hallmarks of myofibroblast activation. Real-time PCR, immunoblots, immunohistochemistry, and flow cytometry analysis performed in whole kidney tissue confirmed increased expression of C1q, C1r, and C1s as well as complement activation, which is measured as increased synthesis of C3 fragments predominantly in the interstitial compartment. Flow studies localized increased C1q expression to PDGFRβ-positive pericytes as well as to CD45-positive cells. Although deletion of C1qA did not prevent kidney fibrosis, global deletion of C3 reduced macrophage infiltration, reduced synthesis of C3 fragments, and reduced fibrosis. Clodronate mediated depletion of CD11bF4/80 high macrophages in UUO mice also reduced complement gene expression and reduced fibrosis. Our studies demonstrate local synthesis of complement by both PDGFRβ-positive pericytes and CD45-positive cells in kidney fibrosis. Inhibition of complement activation represents a novel therapeutic target to ameliorate fibrosis and progression of chronic kidney disease.

scholarly journals HUS and the case for complement

Blood ◽  
2015 ◽  
Vol 126 (18) ◽  
pp. 2085-2090 ◽  
Author(s):  
Edward M. Conway
Keyword(s):  
Escherichia Coli ◽  
Renal Failure ◽  
Shiga Toxin ◽  
Complement Activation ◽  
Thrombotic Microangiopathy ◽  
Response To Treatment ◽  
Microangiopathic Hemolytic Anemia ◽  
New Knowledge ◽  
Uremic Syndrome

Abstract Hemolytic-uremic syndrome (HUS) is a thrombotic microangiopathy that is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. Excess complement activation underlies atypical HUS and is evident in Shiga toxin–induced HUS (STEC-HUS). This Spotlight focuses on new knowledge of the role of Escherichia coli–derived toxins and polyphosphate in modulating complement and coagulation, and how they affect disease progression and response to treatment. Such new insights may impact on current and future choices of therapies for STEC-HUS.

Carboxiterminal pro-endothelin-1 as an endothelial cell biomarker in thrombotic thrombocytopenic purpura

2016 ◽  
Vol 115 (05) ◽  
pp. 1034-1043 ◽  
Author(s):  
György Sinkovits ◽  
Péter Farkas ◽  
Dorottya Csuka ◽  
Katalin Rázsó ◽  
Marienn Réti ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Acute Phase ◽  
Complement Activation ◽  
Endothelial Activation ◽  
Factor H ◽  
Healthy Controls ◽  
Activation Markers ◽  
Thrombocytopenic Purpura ◽  
Endothelin 1

SummaryThrombotic thrombocytopenic purpura (TTP) is characterised by the deficiency of the von Willebrand factor (VWF) cleaving protease (ADAMTS-13). Although several observations indicate an important role of endothelial activation in the pathogenesis of TTP, no reliable endothelial activation markers are available in the clinical management of TTP. Our aim was to investigate the presence of endothelial activation in TTP and to determine its connections with disease activity, therapy and complement activation. We enrolled 54 patients (median age 40.5; 44 females) and 57 healthy controls (median age 34; 30 females),VWF antigen, carboxiterminal-pro-endothelin-1 (CT-proET-1), complement Factor H and complement activation products (C3bBbP and SC5b-9) were measured. In both the acute and remission phase of TTP we found increased CT-proET-1 and VWF levels, while Factor H levels decreased compared with healthy controls. In remission, however, the elevated CT-proET-1 levels showed 22 % decrease when compared with the acute phase in paired samples (p=0.0031), whereas no changes for VWF and Factor H levels were observed. We also found positive correlations between CT-proET-1 levels and alternative pathway activation markers (C3bBbP; p=0.0360; r=0.4299). The data we present here demonstrate a role of endothelium activation in patients with acute TTP. The finding that CT-proET-1 levels decreased in remission compared with the acute phase further supports endothelial involvement. In addition, we show that endothelial activation also correlated with the activation of the alternative complement pathway. The data suggest that complement and endothelium activation jointly contribute to the development of TTP episodes in patients with predisposition to TTP.Supplementary Material to this article is available online at www.thrombosis-online.com.

scholarly journals Complement C1r serine protease contributes to kidney fibrosis

2019 ◽  
Vol 317 (5) ◽  
pp. F1293-F1304 ◽  
Author(s):  
Sandhya Xavier ◽  
Ranjit K. Sahu ◽  
Sai Vineela Bontha ◽  
Valeria Mas ◽  
Ronald P. Taylor ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Complement Activation ◽  
Kidney Tissue ◽  
Growth Factor Receptor ◽  
Tubulointerstitial Fibrosis ◽  
Complement C3 ◽  
Cellular Mechanisms ◽  
Kidney Fibrosis ◽  
Expression Of Genes

We have previously reported that complement activation precedes the development of kidney fibrosis; however, little is known about the cellular mechanisms involved in this transition. We hypothesized that increased expression of C1 complex protease C1r, the initiator of complement activation, contributes to tubulointerstitial fibrosis and tested this idea in mice with global deletion of C1r. Although expression of C1r in untreated wild-type (WT) mice was higher in the liver compared with kidney tissue, administration of folic acid (FA) led to upregulation of C1r mRNA and protein levels only in kidney tissue. Immunohistochemistry and in situ hybridization experiments localized increased expression of C1r and C1s proteases to renal tubular epithelial cells. C1r-null mice had reduced acute tubular injury and inflammation measured 2 days after FA administration compared with WT mice. C1r deletion reduced expression of C1s, C3 fragment formation, and organ fibrosis measured 14 days after FA administration. Differential gene expression performed in kidney tissue demonstrated that C1r-null mice had reduced expression of genes associated with the acute phase response, complement, proliferation of connective tissue cells (e.g., platelet-derived growth factor receptor-β), and reduced expression of genes associated with inflammation compared with FA-treated WT mice. In vitro experiments in renal epithelial cells demonstrated that C1s expression is dependent on increased C1r expression and that interferon-γ induces the expression of these two proteases. We conclude that increased expression of C1 complex proteases is associated with increased tissue inflammation and complement C3 formation and represents an important pathogenic mechanism leading to FA-mediated tubulointerstitial fibrosis.

scholarly journals Eculizumab, a novel potential treatment for acute kidney injury associated with preeclampsia/HELLP syndrome

2019 ◽  
Vol 12 (9) ◽  
pp. e228709 ◽  
Author(s):  
Hatem Elabd ◽  
Mennallah Elkholi ◽  
Lewis Steinberg ◽  
Anjali Acharya
Keyword(s):  
Acute Kidney Injury ◽  
Renal Replacement Therapy ◽  
Replacement Therapy ◽  
Complement Activation ◽  
Hellp Syndrome ◽  
Kidney Injury ◽  
Complement Protein ◽  
Igg Antibody ◽  
Elevated Liver Enzymes

The kidney is one of the major organs affected in preeclampsia. There is evidence suggesting a role for excessive complement activation in the pathogenesis of preeclampsia. We describe a case of preeclampsia with severe features, including HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) and acute kidney injury (AKI) that developed following caesarian section. The patient required renal replacement therapy. A trial of daily plasma exchange was not effective. The patient received a single dose of eculizumab, a humanised monoclonal IgG antibody that binds to complement protein C5. One week post administration of eculizumab, there was significant improvement in haematologic, hepatic and renal function. Blood pressure had normalised and renal replacement therapy was discontinued. The use of eculizumab may have contributed to recovery of kidney function further supporting the role of complement activation in the pathogenesis of preeclampsia and associated AKI.

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