Loss of decay-accelerating factor triggers podocyte injury and glomerulosclerosis

Kidney glomerulosclerosis commonly progresses to end-stage kidney failure, but pathogenic mechanisms are still poorly understood. Here, we show that podocyte expression of decay-accelerating factor (DAF/CD55), a complement C3 convertase regulator, crucially controls disease in murine models of adriamycin (ADR)-induced focal and segmental glomerulosclerosis (FSGS) and streptozotocin (STZ)-induced diabetic glomerulosclerosis. ADR induces enzymatic cleavage of DAF from podocyte surfaces, leading to complement activation. C3 deficiency or prevention of C3a receptor (C3aR) signaling abrogates disease despite DAF deficiency, confirming complement dependence. Mechanistic studies show that C3a/C3aR ligations on podocytes initiate an autocrine IL-1β/IL-1R1 signaling loop that reduces nephrin expression, causing actin cytoskeleton rearrangement. Uncoupling IL-1β/IL-1R1 signaling prevents disease, providing a causal link. Glomeruli of patients with FSGS lack DAF and stain positive for C3d, and urinary C3a positively correlates with the degree of proteinuria. Together, our data indicate that the development and progression of glomerulosclerosis involve loss of podocyte DAF, triggering local, complement-dependent, IL-1β–induced podocyte injury, potentially identifying new therapeutic targets.

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Faculty Opinions recommendation of Focal and segmental glomerulosclerosis induced in mice lacking decay-accelerating factor in T cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1159353.619700 ◽

2009 ◽

Author(s):

Heinz Regele

Keyword(s):

T Cells ◽

Focal And Segmental Glomerulosclerosis ◽

Decay Accelerating Factor ◽

Segmental Glomerulosclerosis

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POS-397 Severe diabetic glomerulosclerosis by chronic hypoxic housing of db/db mice; the role of mesangiolysis and podocyte injury with ultrastructural abnormalities

Kidney International Reports ◽

10.1016/j.ekir.2021.03.415 ◽

2021 ◽

Vol 6 (4) ◽

pp. S171

Author(s):

N. Takahashi ◽

H. Yoshida ◽

H. Kimura ◽

K. Kamiyama ◽

T. Kurose ◽

...

Keyword(s):

Diabetic Glomerulosclerosis ◽

Podocyte Injury

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Decay-Accelerating Factor Suppresses Complement C3 Activation and Retards Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice

American Journal Of Pathology ◽

10.2353/ajpath.2009.090183 ◽

2009 ◽

Vol 175 (4) ◽

pp. 1757-1767 ◽

Cited By ~ 32

Author(s):

Viola W.Y. Leung ◽

Sheng Yun ◽

Marina Botto ◽

Justin C. Mason ◽

Talat H. Malik ◽

...

Keyword(s):

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Complement C3 ◽

Low Density ◽

Lipoprotein Receptor ◽

Low Density Lipoprotein Receptor ◽

Decay Accelerating Factor ◽

Density Lipoprotein Receptor ◽

Deficient Mice

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Expression of decay accelerating factor mRNA and complement C3 mRNA in human diseased kidney

Kidney International ◽

10.1046/j.1523-1755.1998.00961.x ◽

1998 ◽

Vol 54 (1) ◽

pp. 120-130 ◽

Cited By ~ 34

Author(s):

Katsushige Abe ◽

Masanobu Miyazaki ◽

Takehiko Koji ◽

Akira Furusu ◽

Yoshiyuki Ozono ◽

...

Keyword(s):

Complement C3 ◽

Decay Accelerating Factor ◽

Diseased Kidney

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Generation and characterization of Ccdc28b mutant mice links the Bardet-Biedl associated gene with social behavioral phenotypes

10.1101/2021.10.21.465251 ◽

2021 ◽

Author(s):

Matías Fabregat ◽

Sofía Niño ◽

Sabrina Pose ◽

Magdalena Cárdenas-Rodríguez ◽

Corrine Smolen ◽

...

Keyword(s):

Coiled Coil ◽

Causal Link ◽

Autism Spectrum ◽

Phenotypic Characterization ◽

Murine Models ◽

Phenotypic Analysis ◽

Behavioral Phenotypes ◽

Mild Phenotype ◽

Bardet Biedl Syndrome

CCDC28B (coiled-coil domain-containing protein 28B) was identified as a modifier in the ciliopathy Bardet-Biedl syndrome (BBS). Our previous work in cells and zebrafish showed that CCDC28B plays a role regulating cilia length in a mechanism that is not completely understood. Here we report the generation of a Ccdc28b mutant mouse using CRISPR/Cas9 (Ccdc28b mut). After confirming the depletion of Ccdc28b ;we performed a phenotypic characterization showing that Ccdc28b mut animals present a mild phenotype: i) do not present clear structural cilia affectation, although we did observe mild defects in cilia density and cilia length in some tissues, ii) reproduce normally, and iii) do not develop retinal degeneration or obesity, two hallmark features of reported BBS murine models. In contrast, Ccdc28b mut mice did show clear social interaction defects as well as stereotypical behaviors suggestive of autism spectrum disorder (ASD). This finding is indeed relevant regarding CCDC28B as a modifier of BBS since behavioral phenotypes have been documented in BBS. Importantly however, our data suggests a possible causal link between CCDC28B and ASD-like phenotypes that exceeds the context of BBS: filtering for rare deleterious variants, we found CCDC28B mutations in eight probands from the Simmons Simplex Collection cohort. Furthermore, a phenotypic analysis showed that CCDC28B mutation carriers present lower BMI and mild communication defects compared to a randomly selected sample of SSC probands. Thus, our results suggest that mutations in CCDC28B lead to mild autism-like features in mice and humans. Overall, this work reports a novel mouse model that will be key to continue evaluating genetic interactions in BBS, deciphering the contribution of CCDC28B to modulate the presentation of BBS phenotypes. In addition, our data underscores a novel link between CCDC28B and ASD-like phenotypes, providing a novel opportunity to further our understanding of the genetic, cellular, and molecular basis of ASD.

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Gain-of-function factor H–related 5 protein impairs glomerular complement regulation resulting in kidney damage

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2022722118 ◽

2021 ◽

Vol 118 (13) ◽

pp. e2022722118

Author(s):

Talat H. Malik ◽

Daniel P. Gitterman ◽

Deborah P. Lavin ◽

Hannah J. Lomax-Browne ◽

E. Christina Hiemeyer ◽

...

Keyword(s):

Significant Proportion ◽

Kidney Injury ◽

Factor H ◽

Complement C3 ◽

Definitive Treatment ◽

Gain Of Function ◽

Adeno Associated Virus ◽

Superior Surface ◽

Stage Renal Disease ◽

End Stage

Genetic variation within the factor H–related (FHR) genes is associated with the complement-mediated kidney disease, C3 glomerulopathy (C3G). There is no definitive treatment for C3G, and a significant proportion of patients develop end-stage renal disease. The prototypical example is CFHR5 nephropathy, through which an internal duplication within a single CFHR5 gene generates a mutant FHR5 protein (FHR5mut) that leads to accumulation of complement C3 within glomeruli. To elucidate how abnormal FHR proteins cause C3G, we modeled CFHR5 nephropathy in mice. Animals lacking the murine factor H (FH) and FHR proteins, but coexpressing human FH and FHR5mut (hFH-FHR5mut), developed glomerular C3 deposition, whereas mice coexpressing human FH with the normal FHR5 protein (hFH-FHR5) did not. Like in patients, the FHR5mut had a dominant gain-of-function effect, and when administered in hFH-FHR5 mice, it triggered C3 deposition. Importantly, adeno-associated virus vector-delivered homodimeric mini-FH, a molecule with superior surface C3 binding compared to FH, reduced glomerular C3 deposition in the presence of the FHR5mut. Our data demonstrate that FHR5mut causes C3G by disrupting the homeostatic regulation of complement within the kidney and is directly pathogenic in C3G. These results support the use of FH-derived molecules with enhanced C3 binding for treating C3G associated with abnormal FHR proteins. They also suggest that targeting FHR5 represents a way to treat complement-mediated kidney injury.

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Effects of BSF on Podocyte Apoptosis via Regulating the ROS-Mediated PI3K/AKT Pathway in DN

Journal of Diabetes Research ◽

10.1155/2019/9512406 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10

Author(s):

Fang-qiang Cui ◽

Yue-Fen Wang ◽

Yan-bin Gao ◽

Yuan Meng ◽

Zhen Cai ◽

...

Keyword(s):

In Vitro Studies ◽

Akt Pathway ◽

Sirna Transfection ◽

Podocyte Injury ◽

Nitrogen Levels ◽

Stage Renal Disease ◽

End Stage ◽

Protein Serum

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). The ROS-mediated PI3K/AKT pathway plays a key role in podocyte apoptosis and DN progression. Our previous study demonstrated that Baoshenfang (BSF) can decrease proteinuria and attenuate podocyte injury. However, the effects of BSF on podocyte apoptosis induced by the ROS-mediated PI3K/AKT pathway remain unclear. Herein, in vivo and in vitro studies have been performed. In our in vivo study, BSF significantly decreased 24-h urinary protein, serum creatinine, and blood urea nitrogen levels in DN mice. Meanwhile, BSF significantly inhibited oxidative stress and podocyte apoptosis in our in vivo and in vitro studies. Moreover, BSF significantly decreased the inhibition of the PI3K/AKT pathway induced by HG in DN. More importantly, the effects of BSF on podocyte apoptosis were reversed by PI3K siRNA transfection. In conclusion, BSF can decrease proteinuria and podocyte apoptosis in DN, in part through regulating the ROS-mediated PI3K/AKT pathway.

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NADPH Oxidase-Induced NALP3 Inflammasome Activation Is Driven by Thioredoxin-Interacting Protein Which Contributes to Podocyte Injury in Hyperglycemia

Journal of Diabetes Research ◽

10.1155/2015/504761 ◽

2015 ◽

Vol 2015 ◽

pp. 1-12 ◽

Cited By ~ 25

Author(s):

Pan Gao ◽

Fang-Fang He ◽

Hui Tang ◽

Chun-Tao Lei ◽

Shan Chen ◽

...

Keyword(s):

Nadph Oxidase ◽

Antioxidant Defense System ◽

Inflammasome Activation ◽

Podocyte Injury ◽

Interacting Protein ◽

Nalp3 Inflammasome ◽

Thioredoxin Interacting Protein ◽

A Subunit ◽

Stage Renal Disease ◽

End Stage

Diabetic nephropathy (DN) is one of the major causes of end-stage renal disease, and previously we demonstrated that NALP3 inflammasome was involved in the pathogenesis of DN. Here we investigated the mechanisms of NALP3 inflammasome activation in podocyte injury during DN. We found that, besides the activation of NALP3 inflammasome and upregulated thioredoxin-interacting protein (TXNIP), the glomerular expression ofgp91phox, a subunit of NADPH oxidase, was enhanced in DN mice simultaneously. Inhibiting NADPH oxidase abrogated NALP3 inflammasome activation, and IL-1βproduction and eventually protected podocytes from high glucose- (HG-) induced injury. TXNIP, an inhibitor of thioredoxin, acts as a suppressor for antioxidant defense system. Our observation indicated that in HG-exposed podocytes genetic deletion of TXNIP by shRNA reversedgp91phoxoverexpression and alleviated the injury of podocyte. Collectively, our findings proposed that HG-induced NADPH oxidase activation was driven by TXNIP which subsequently triggered NALP3 inflammasome activation in podocytes and ultimately led to podocyte injury, and blocking TXNIP/NADPH oxidase signaling may be a promising treatment for DN.Erratum to “NADPH Oxidase-Induced NALP3 Inflammasome Activation Is Driven by Thioredoxin-Interacting Protein Which Contributes to Podocyte Injury in Hyperglycemia”

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A prevalent C3 mutation in aHUS patients causes a direct C3 convertase gain of function

Blood ◽

10.1182/blood-2011-10-383281 ◽

2012 ◽

Vol 119 (18) ◽

pp. 4182-4191 ◽

Cited By ~ 87

Author(s):

Lubka T. Roumenina ◽

Marie Frimat ◽

Elizabeth C. Miller ◽

Francois Provot ◽

Marie-Agnes Dragon-Durey ◽

...

Keyword(s):

At Risk ◽

Atypical Hemolytic Uremic Syndrome ◽

Factor H ◽

Complement C3 ◽

Rapid Progression ◽

Incomplete Penetrance ◽

Inflammatory Stimuli ◽

Uremic Syndrome ◽

Stage Renal Disease ◽

End Stage

Abstract Atypical hemolytic uremic syndrome (aHUS) is a rare renal thrombotic microangiopathy commonly associated with rare genetic variants in complement system genes, unique to each patient/family. Here, we report 14 sporadic aHUS patients carrying the same mutation, R139W, in the complement C3 gene. The clinical presentation was with a rapid progression to end-stage renal disease (6 of 14) and an unusually high frequency of cardiac (8 of 14) and/or neurologic (5 of 14) events. Although resting glomerular endothelial cells (GEnCs) remained unaffected by R139W-C3 sera, the incubation of those sera with GEnC preactivated with pro-inflammatory stimuli led to increased C3 deposition, C5a release, and procoagulant tissue-factor expression. This functional consequence of R139W-C3 resulted from the formation of a hyperactive C3 convertase. Mutant C3 showed an increased affinity for factor B and a reduced binding to membrane cofactor protein (MCP; CD46), but a normal regulation by factor H (FH). In addition, the frequency of at-risk FH and MCP haplotypes was significantly higher in the R139W-aHUS patients, compared with normal donors or to healthy carriers. These genetic background differences could explain the R139W-aHUS incomplete penetrance. These results demonstrate that this C3 mutation, especially when associated with an at-risk FH and/or MCP haplotypes, becomes pathogenic following an inflammatory endothelium-damaging event.

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