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Deficiency of CFB attenuates renal tubulointerstitial damage via inhibiting ceramide synthesis in diabetic kidney disease

ABSTRACT: Deficiency of CFB attenuates renal tubulointerstitial damage via inhibiting ceramide synthesis in diabetic kidney disease

PROVIDER: PRJNA897751 | ENA |

REPOSITORIES: ENA

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	SRR22164409_1.fastq.gz	Fastqsanger.gz
	SRR22164409_2.fastq.gz	Fastqsanger.gz
	SRR22164410_1.fastq.gz	Fastqsanger.gz
	SRR22164410_2.fastq.gz	Fastqsanger.gz
	SRR22164411_1.fastq.gz	Fastqsanger.gz

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Deficiency of CFB attenuates renal tubulointerstitial damage via inhibiting ceramide synthesis in diabetic kidney disease

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.

2023-02-01 | GSE217153 | GEO

Deficiency of CFB attenuates renal tubulointerstitial damage by inhibiting ceramide synthesis in diabetic kidney disease.

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, the staining of Bb, CFB, C3a, C5a, and C5b-9 was markedly elevated in renal tubulointerstitium. Cfb-knockout diabetic mice had substantially 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 HK-2 cells transfected with siRNA of CFB 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, by 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.

| S-EPMC9869976 | biostudies-literature

Fatty acid transport protein 2 interacts with ceramide synthase 2 to regulate ceramide synthesis

Project description:Dihydroceramide is generated via the action of (dihydro)ceramide synthases (CerSs), which use two substrates, namely sphinganine and fatty acyl CoAs. Sphinganine is generated via the sequential activity of two integral membrane proteins located in the endoplasmic reticulum. Less is known about the source of supply of the fatty acyl CoAs, although a number of cytosolic proteins in the pathways of acyl CoA generation have been shown to modulate ceramide synthesis via direct or indirect interaction with the CerSs. We now demonstrate, by proteomic analysis of immunoprecipitated proteins, that fatty acid transporter protein 2 (FATP2) (also known as very long-chain acyl-CoA synthetase) directly interacts with CerS2 in mouse liver. Studies in cultured cells demonstrated that other members of the FATP family can also interact with CerS2, with the interaction dependent on both proteins being catalytically active. Transfection of cells with FATP1, FATP2 or FATP4 increased ceramide levels although only FATP2 and 4 increased dihydroceramide levels, consistent with their known intracellular locations. Finally, lipofermata, an FATP2 inhibitor which is believed to directly impact tumor cell growth via modulation of FATP2, decreased de novo dihydroceramide synthesis, suggesting that some of the proposed therapeutic effects of lipofermata may actually be mediated via (dihydro)ceramide rather than directly via acyl CoA generation

2022-04-04 | PXD031088 | Pride

Cdk8 attenuates lipogenesis by inhibiting SREBP-dependent transcription in Drosophila

Project description:Cdk8 attenuates lipogenesis by inhibiting SREBP-dependent transcription in Drosophila

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Paraspeckle protein NONO attenuates vascular calcification by inhibiting BMP2 transcription

Project description:Paraspeckle protein NONO attenuates vascular calcification by inhibiting BMP2 transcription

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Aging stress and ceramide dependent RNA sequencing expression profiling depends on ceramide synthase 6

Project description:The bioactive sphingolipid ceramide, generated by ceramide synthase, is an adaptive stress effector induced in response to various stress stimuli such as aging. In fact, ceramide synthase (CerS) was first discovered in yeast as a longevity assurance gene (LAG1), as the reduced ceramide generation consequent to LAG1 deletion increased longevity. There are six homologues of mammalian LAG1/ceramide synthases (CerS1-6) that generate ceramides with different fatty acid chain lengths with distinct functions and hydrophobicity. Ceramide can be metabolized by sphingosine kinase 1 or 2 for the generation of pro-survival sphingosine 1-phosphate (S1P), which enhances immune cell egress to the blood stream, activating immune function. Ceramide is known to induce mitophagy and cell death. Here we investigated the role of this sphingolipid pathway in immune function, specifically T cell functions, via high throughput expression profiling.

2021-01-01 | GSE148498 | GEO

Secretory Leukocyte Peptidase Inhibitor (SLPI) is a Novel Predictor of Tubulointerstitial Injury and Renal Outcome in Patients with Diabetic Nephropathy

Project description:Tubulointerstitial injury plays an important role in diabetic nephropathy (DN) progression; however, no reliable urinary molecule has been used to predict tubulointerstitial injury and renal outcome of DN clinically. In this study, based on tubulointerstitial transcriptome, we identified secretory leukocyte peptidase inhibitor (SLPI) as the molecule associated with renal fibrosis and prognosis of DN. In tubular cells, high glucose could upregulate SLPI, which bound with β-catenin and GSK-3β reciprocally, abolished the interaction between β-catenin and GSK-3β, diminished GSK-3β-regulated β-catenin phosphorylation and the subsequent ubiquitination and degradation, thus led to β-catenin signaling activation and renal fibrosis. Db/db mice injected with adenovirus carrying Slpi-3xflag-GFP (Ad-Slpi-GFP) developed β-catenin signaling activation in the proximal tubule, worse albuminuria and tubulointerstitial fibrosis. Conversely, Slpi knockout (KO) mice with STZ-induced DN developed less albuminuria, tubulointerstitial fibrosis and β-catenin signaling activation. Furthermore, clinical studies showed that urinary SLPI protein level (uSLPI/Cr) had significant correlation with intrarenal SLPI mRNA and interstitial fibrosis. In an independent prospective cohort enrolled 711 patients with biopsy proven DN, uSLPI/Cr level was significantly associated with eGFR slope and improved the prediction value of renal outcome. Together, our study identified SLPI as a novel critical regulator for the progression of tubulointerstitial injury, which may be used as an independent risk predictor of DN progression.

2022-08-03 | GSE158230 | GEO

MYT1 attenuates neuroblastoma cell differentiation by inhibiting retinoic acid signaling pathway

Project description:MYT1 attenuates neuroblastoma cell differentiation by inhibiting retinoic acid signaling pathway

| PRJNA526212 | ENA

Opportunistic pathogen Porphyromonas gingivalis targets the LC3B-ceramide complex and mediates lethal mitophagy resistance in oral tumors

Project description:Mechanisms by which Porphyromonas gingivalis (P. gingivalis) infection enhances oral tumor growth or resistance to cell death remain elusive. Here, we determined that P. gingivalis infection mediates therapeutic resistance via inhibiting lethal mitophagy in cancer cells and tumors. Mechanistically, P. gingivalis targets the LC3B-ceramide complex by associating with LC3B via bacterial major fimbriae (FimA) protein, preventing ceramide-dependent mitophagy in response to various therapeutic agents. Moreover, ceramide-mediated mitophagy is induced by Annexin A2 (ANXA2)-ceramide association, involving the E142 residue of ANXA2. Inhibition of ANXA2-ceramide-LC3B complex formation by wild-type P. gingivalis prevented ceramide-dependent mitophagy. Moreover, a FimA-deletion mutant P. gingivalis variant had no inhibitory effects on ceramide-dependent mitophagy. Further, 16S rRNA sequencing of oral tumors indicated that P. gingivalis infection altered the microbiome of the tumor macroenvironment in response to ceramide analog treatment in mice. Thus, these data provide a mechanism describing the pro-survival roles of P. gingivalis in oral tumors.

2024-06-23 | PXD051568 | Pride

Pimobendan attenuates pressure overload-induced myocardial hypertrophy by inhibiting the MAPKs pathway

Project description:Pimobendan attenuates pressure overload-induced myocardial hypertrophy by inhibiting the MAPKs pathway

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