Complement C5a/C5a receptor 1 induces renal injury in diabetic kidney disease via mitochondrial metabolic reprogramming
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ABSTRACT:
PROVIDER: PRJNA484388 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7642020.fastq.gz | Fastqsanger.gz | |||
| SRR7642030.fastq.gz | Fastqsanger.gz | |||
| SRR7642021.fastq.gz | Fastqsanger.gz | |||
| SRR7642012.fastq.gz | Fastqsanger.gz | |||
| SRR7642022.fastq.gz | Fastqsanger.gz |
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Project description:In mice, complement C5a and its receptor C5aR1 elicit systemic and local inflammation and drive tissue injury in diabetic kidney disease via altered metabolic flexibility, which can be attenuated by therapy with a specific orally active inhibitor of C5aR1.
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Project description:Epigenetic mechanisms as DNA methylation can affect allograft outcome after kidney transplantation, accelerating renal aging. Complement system is the major player of ischemia reperfusion (I/R) injury and Renal Proximal Tubular Cells (RPTEC) are known to express C5a receptor (C5aR). However, little is known about the downstream effect of C5a-C5aR interaction. We performed a whole-genome DNA methylation analysis on C5a stimulated RPTEC and found several regions regulating genes involved in cell cycle control, DNA damage checkpoints and WNT signaling. These most represented genes were BCL9, CYP1B1 and CDK6. We showed that C5a induced-aberrant gene methylation significantly influences the expression of these genes. Moreover, the stimulation of RTEC by C5a led to senescence by up-regulating SA-β Gal positivity and increasing p53 gene and p21 protein level. IL-6, MCP-1, CTGF gene levels increase indicated the tubular SASP (Senescence associated Secretory Phenotype) acquirement. In accordance, in a swine model of I/R injury, we found that the increase expression of WNT4/βcatenin expression correlated with the augment in SA-β Gal, p21, p16 and IL-6 positivity after 24h from reperfusion. The treatment with C1-INH, a complement inhibitor, efficiently antagonized SASP restoring SA-β Gal, p21, p16, IL-6 expression at basal level and abrogating the WNT4/βcatenin activation. Thus, C5a affects the DNA methylation of genes involved in tubular senescence leading to a persistent, low-grade, inflammatory state called inflammaging. Targeting epigenetic programs may offer novels strategies to protect tubular cells from aging and promote kidney repair and recovery.
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Project description:Accumulating evidence suggests the pathogenic role of immunity and metabolism in diabetic kidney disease (DKD). Herein, we aimed to investigate the effect of complement factor B (CFB) on lipid metabolism in the development of DKD. We found that in patients with diabetic nephropathy (DN), the staining of Bb, CFB, C3a, C5a, and C5b-9 were significantly elevated in renal tubulointerstitium. Cfb knockout diabetic mice had significantly milder tubulointerstitial injury and less ceramide biosynthesis. The in vitro study demonstrated that cytokine secretion, endoplasmic reticulum stress, oxidative stress, and cell apoptosis were ameliorated in siCFB HK-2 cells under high glucose conditions. Exogenous ceramide supplementation attenuated the protective effect of CFB knockdown in HK-2 cells, while inhibiting ceramide synthases (CERS) with fumonisin B1 in CFB-overexpressing cells rescued the cell injury. CFB knockdown could downregulate the expression of NF-κB p65, which initiates the transcription of CERS3. Furthermore, C3 knockdown abolished CFB-mediated cytokine secretion, NF-κB signaling activation, and subsequently ceramide biosynthesis. Thus, CFB deficiency inhibited activation of the complement alternative pathway and attenuated kidney damage in DKD, especially tubulointerstitial injury, via inhibiting the NF-κB signaling pathway, further blocking the transcription of CERS, which regulates the biosynthesis of ceramide. CFB may be a promising therapeutic target of DKD.
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Project description:Critical illness is characterised by organ failure, dysregulated immune activation and frequent secondary infections. Unbridled complement activation in these patients exposes immune cells to high levels of the anaphylotoxin, C5a. C5a suppresses antimicrobial functions of key immune cells, in particular the neutrophil, and this suppression is associated with poorer outcomes amongst critically ill adults. The intracellular signalling pathways which mediate C5a-induced neutrophil dysfunction are incompletely understood. Healthy donor peripheral blood neutrophils exposed to purified C5a demonstrated a prolonged defect in phagocytosis of the common nosocomial pathogen Staphylococcus aureus which persisted for 7 hours after exposure. Phosphoproteomic profiling of 2712 unique phosphoproteins identified persistent C5a signalling at 1 hour, and selective impairment of phagosomal protein phosphorylation on exposure to S. aureus. Notable proteins included early endosomal marker ZFYVE16 and V-ATPase proton channel component ATPV1G1. A multi-function assay of bacterial ingestion and phagosomal acidification demonstrated C5a-induced impairment of phagosomal acidification in a whole blood model of Staphylococcal bacteraemia which was recapitulated in neutrophils from critically ill patients. Examination of the C5a-impaired protein phosphorylation indicated a role for the phosphatidylinositol 3-kinase VPS34 in phagosomal maturation. Inhibition of VPS34 impaired neutrophil phagosomal acidification, late bacterial ingestion and killing of S. aureus in whole blood. This study provides a deep phosphoproteomic assessment of human neutrophil signalling in response to S. aureus, and demonstrates how some of these pathways are disrupted by exposure to C5a, identifying a defect in phagosomal maturation and providing new information on mechanisms of immune failure in critical illness.
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Project description:Diabetic kidney disease (DKD) has become the leading cause of end-stage renal disease worldwide. Therefore, efforts to understand DKD pathophysiology and prevent its development are highly warranted. Here, we analyzed renal cortex from healthy mice, diabetic mice, and diabetic mice treated with the Hippo signaling pathway inhibitor XMU-MP-1. Our study first confirmed that XMU-MP-1 improved DKD in type 2 diabetic mice induced by high-fat diet feeding and intraperitoneal injection of streptozotocin. Through RNA-sequencing of isolated renal cortex, we found that activation of the Hippo signaling pathway, chemokine signaling pathway and cell activation involved in immune response were positively associated with the progression of DKD, while mitochondrion organization was negatively associated with the development of DKD. By contrast, administration of XMU-MP-1 partly suppressed the irritation of chemokine signaling pathway, and organ or tissue specific immune response, but preserved mitochondrion organization within renal cortex of DKD. In vitro, cell culture of immortalized renal tubule cells revealed that overexpression of yes-associated protein 1, the downstream core mediator of the Hippo signaling pathway, reduced high glucose and palmitic acid-induced tubule cell impairment by improving the maintenance of mitobiogenesis and mitophagy. Overall, our data emphasize that the renal protective effects of suppressing Hippo signaling pathway are likely through preserving the mitochondrial quality control homeostasis in tubule cells.
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Project description:OVE26 (OVE) mice provide a useful model of advanced diabetic nephropathy (DN) with respect to albuminuria and pathologies. We showed that albuminuria, reduced GFR and interstitial fibrosis, which normally take 8-9 months to develop, are more advanced in uninephrectomized OVE mice within 10 weeks of surgery, at 4.5 months of age. The accelerated progression of renal damage, especially renal fibrosis in OVE-uni mice, was also identified at the gene expression level. The hepatic fibrosis/hepatic stellate cell activation pathway was by far the most significant Ingenuity canonical pathway identified by gene array in OVE-uni mice. Many inflammatory- and immune-related pathways were found among the top pathways up-regulated in OVE-uni kidneys, including acute-phase response signaling, leukocyte extravasation, IL6, IL10, IL12 signaling, TREM1 signaling, dendritic cell maturation and the complement system. These pathways were also dramatically up-regulated in 8-month-old OVE mice (GSE20636). Nephrectomized OVE mice are a much faster alternative model for studying advanced renal disease in diabetes. Study of renal gene expression in diabetic OVE26 mice. Uninephrectomy was used as an accelerating factor. Pooled RNA samples from 4 individual mice in each treatment group (OVE-uni, OVE-sham, FVB-uni, FVB-sham) were used for probe hybridization. Treatment groups: OVE-uni: uninephrectomy treatment in diabetic mice OVE-sham: sham surgery treatment in diabetic mice FVB-uni: uninephrectomy treatment in nondiabetic mice FVB-sham: sham surgery treatment in nondiabetic mice
2011-04-15 | E-GEOD-21448 | biostudies-arrayexpress
Project description:We investigated the gene expression profiles of RNA isolated from kidney glomeruli and renal tubules from aged, 24 week old type-2 diabetic (db/db) and non-diabetic mice
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Project description:Expression data from primary human neutrophils incubated with complement anaphylatoxin C5a
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