Podocytes Produce and Secrete Functional Complement C3 and Complement Factor H

Mühlig, Anne K; Keir, Lindsay; Abt, Jana C; Heidelbach, Hannah S; Horton, Rachel Elizabeth; Welsh, Gavin I.; Meyer-Schwesinger, Catherine; Licht, Christoph; Coward, Richard J M; Fester, Lars; Saleem, Moin A.; Oh, Jun

doi:10.3389/fimmu.2020.01833

Cited by 22 publications

(18 citation statements)

References 87 publications

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Section: C3 Fragments As Markers Of Complement Activation In Kidney Cellssupporting

confidence: 90%

“…We demonstrated the accumulation of C3 fragments including C3b, iC3b in whole kidney tissue homogenates and primary cell cultures of renal epithelial cells and pericytes (Figure 1). More recently, it was demonstrated that podocytes produce functional C3 and are a local source for glomerular complement activation (Muhlig et al, 2020). Our results using C3‐deficient mice support a previous report of reduced fibrosis in these mice (X. Zhou et al, 2013) but also extend this observation by showing that the lack of C3 expression in kidney tissue was accompanied by reduced deposition of active C3 fragments in the interstitial space and reduced infiltration of inflammatory cells, including macrophages.…”

Section: C3 Fragments As Markers Of Complement Activation In Kidney Cellsmentioning

confidence: 99%

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Role of intracellular complement activation in kidney fibrosis

Portilla

Xavier

2021

British J Pharmacology

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Increased expression of complement C1r, C1s and C3 in kidney cells plays an important role in the pathogenesis of kidney fibrosis. Our studies suggest that activation of complement in kidney cells with increased generation of C3 and its fragments occurs by activation of classical and alternative pathways. Single nuclei RNA sequencing studies in kidney tissue from unilateral ureteral obstruction mice show that increased synthesis of complement C3 and C5 occurs primarily in renal tubular epithelial cells (proximal and distal), while increased expression of complement receptors C3ar1 and C5ar1 occurs in interstitial cells including immune cells like monocytes/macrophages suggesting compartmentalization of complement components during kidney injury. Although global deletion of C3 and macrophage ablation prevent inflammation and reduced kidney tissue scarring, the development of mice with cell‐specific deletion of complement components and their regulators could bring further insights into the mechanisms by which intracellular complement activation leads to fibrosis and progressive kidney disease. Linked Articles This article is part of a themed issue on Canonical and non‐canonical functions of the complement system in health and disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.14/issuetoc

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Section: C3 Fragments As Markers Of Complement Activation In Kidney Cellssupporting

confidence: 90%

Section: C3 Fragments As Markers Of Complement Activation In Kidney Cellsmentioning

confidence: 99%

Role of intracellular complement activation in kidney fibrosis

Portilla

Xavier

2021

British J Pharmacology

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“…CFAH, an abundant serum glycoprotein, is one of the most important circulating regulators of the alternative pathway. It is expressed constitutively in liver and locally expressed by endothelial cells, epithelial cells, and podocytes [ 33 ]. CFAH serves as an essential cofactor for CFAI-mediated C3b cleavage.…”

Section: Discussionmentioning

confidence: 99%

“…In cultured immortalized human podocytes and primary human podocytes from a known Arg1182Ser (G3546T) CFAH mutant patient, CFAH was confirmed to be expressed by podocytes. Moreover, expression of CFAH was up-regulated in injured podocytes [ 33 ]. As a molecule of 150 kDa, CFAH is prevented from filtration by a healthy glomerular filtration barrier.…”

Section: Discussionmentioning

confidence: 99%

Urinary complement proteins and risk of end-stage renal disease: quantitative urinary proteomics in patients with type 2 diabetes and biopsy-proven diabetic nephropathy

Zhao

Zhang

Liu

et al. 2021

J Endocrinol Invest

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Purpose To investigate the association between urinary complement proteins and renal outcome in biopsy-proven diabetic nephropathy (DN). Methods Untargeted proteomic and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analyses and targeted proteomic analysis using parallel reaction-monitoring (PRM)-mass spectrometry was performed to determine the abundance of urinary complement proteins in healthy controls, type 2 diabetes mellitus (T2DM) patients, and patients with T2DM and biopsy-proven DN. The abundance of each urinary complement protein was individually included in Cox proportional hazards models for predicting progression to end-stage renal disease (ESRD). Results Untargeted proteomic and functional analysis using the KEGG showed that differentially expressed urinary proteins were primarily associated with the complement and coagulation cascades. Subsequent urinary complement proteins quantification using PRM showed that urinary abundances of C3, C9, and complement factor H (CFAH) correlated negatively with annual estimated glomerular filtration rate (eGFR) decline, while urinary abundances of C5, decay-accelerating factor (DAF), and CD59 correlated positively with annual rate of eGFR decline. Furthermore, higher urinary abundance of CFAH and lower urinary abundance of DAF were independently associated with greater risk of progression to ESRD. Urinary abundance of CFAH and DAF had a larger area under the curve (AUC) than that of eGFR, proteinuria, or any pathological parameter. Moreover, the model that included CFAH or DAF had a larger AUC than that with only clinical or pathological parameters. Conclusion Urinary abundance of complement proteins was significantly associated with ESRD in patients with T2DM and biopsy-proven DN, indicating that therapeutically targeting the complement pathway may alleviate progression of DN.

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“…However, this effect would be lower if albumin reabsorption was disrupted (e.g., in nephrotic syndrome) ( 47 ). Moreover, several complement precursors are like albumin ligands for megalin-cubilin receptors and thus also undergo endocytic uptake, and tubular cells and podocytes can synthetize C3, which might add to intratubular C3 ( 48 , 49 ). Plasma albumin levels within the normal range indicate that liver synthesis function was intact.…”

Section: Discussionmentioning

confidence: 99%

Proteinuria is accompanied by intratubular complement activation and apical membrane deposition of C3dg and C5b-9 in kidney transplant recipients

Isaksson

Nielsen

Hinrichs

et al. 2022

American Journal of Physiology-Renal Physiology

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Proteinuria predicts accelerated decline in kidney function in kidney transplant recipients (KTRs). We hypothesized that aberrant filtration of complement factors causes intraluminal activation, apical membrane attack on tubular cells and progressive injury. Biobanked samples from two previous studies in albuminuric KTRs were used. Complement activation split products C3c, C3dg and sC5b-9 associated C9 neoantigen were analyzed by ELISA in urine and plasma using neoepitope-specific antibodies. Urinary extracellular vesicles (uEV) were enriched by lectin- and immunoaffinity-isolation and analyzed by immunoblotting. Urine complement excretion increased significantly in KTRs with albumin/creatinine ratio ≥ 300 mg/g compared to < 30 mg/g. Urine C3dg and C9 neoantigen excretion correlated significantly to changes in albumin excretion from 3 to 12 months after transplantation. The fractional excretion of C9 neoantigen was significantly higher than for albumin indicating post-filtration generation. C9 neoantigen was detected in uEVs in six of nine of albuminuric KTRs but was absent in non-albuminuric controls (n = 8). In C9 neoantigen positive KTRs, lectin-affinity enrichment of uEVs from the proximal tubules yielded signal for iC3b, C3dg, C9 neoantigen and SGLT2 but only weakly for AQP2. Co-isolation of podocyte markers and Tamm-Horsfall protein was minimal. Our findings show that albuminuria is associated with aberrant filtration and intratubular activation of complement with deposition of C3 activation split products and C5b-9 associated C9 neoantigen on uEVs from the proximal tubular apical membrane. Intratubular complement activation may contribute to progressive kidney injury in proteinuric kidney grafts.

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Podocytes Produce and Secrete Functional Complement C3 and Complement Factor H

Cited by 22 publications

References 87 publications

Role of intracellular complement activation in kidney fibrosis

Role of intracellular complement activation in kidney fibrosis

Urinary complement proteins and risk of end-stage renal disease: quantitative urinary proteomics in patients with type 2 diabetes and biopsy-proven diabetic nephropathy

Proteinuria is accompanied by intratubular complement activation and apical membrane deposition of C3dg and C5b-9 in kidney transplant recipients

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