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NNMT overexpression promotes tubular senescence and fibrosis in human chronic kidney disease (Nnmt overexpressing TEC cells) [Series_3]

ABSTRACT: Renal tubular epithelial cells (TECs) are increasingly recognized as the central locus of chronic kidney disease and renal fibrosis. Here, we used conditionally immortalized TECs (expressing SV40 large T antigen at permissive conditions, 33°C with IFNγ, and behaving like normal primary cultures after 7 days in restrictive conditions, 37°C without IFNγ) and genetically overexpressed Nnmt (Nnmt-OE) by means of lentiviral transduction of a mock or Nnmt expression construct. In the TGFβ model mimicking the senescent and pro-fibrotic changes in TECs, Nnmt overexpression resulted in an aggravated phenotype.

ORGANISM(S): Mus musculus

PROVIDER: GSE280552 | GEO | 2025/11/20

REPOSITORIES: GEO

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NNMT overexpression promotes tubular senescence and fibrosis in human chronic kidney disease (NNMT inhibition and SAM supplementation in TEC cells)

Project description:Renal tubular epithelial cells (TECs) are increasingly recognized as the central locus of chronic kidney disease and renal fibrosis. Here, we used conditionally immortalized TECs (expressing SV40 large T antigen at permissive conditions, 33°C with IFNγ, and behaving like normal primary cultures after 7 days in restrictive conditions, 37°C without IFNγ), stimulated with TGFβ to mimic the senescent and pro-fibrotic phenotypic shift of TECs during kidney disease. TGFβ stimulation and co-treatment with either the small-molecule NNMT inhibitor 5-amino-1-methylquinolinium iodide (NNMTi) or S-adenosyl methionine (SAM) altered the DNA methylation profile of the cells.

2025-11-20 | GSE310712 | GEO

NNMT overexpression promotes tubular senescence and fibrosis in human chronic kidney disease (NNMT inhibition in TEC cells) [Series_1]

Project description:Renal tubular epithelial cells (TECs) are increasingly recognized as the central locus of chronic kidney disease and renal fibrosis. Here, we used conditionally immortalized TECs (expressing SV40 large T antigen at permissive conditions, 33°C with IFNγ, and behaving like normal primary cultures after 7 days in restrictive conditions, 37°C without IFNγ), stimulated with TGFβ to mimic the senescent and pro-fibrotic phenotypic shift of TECs during kidney disease. Co-treating the cells with the selective and membrane-permeable small molecule 5-amino-1-methylquinolinium iodide (NNMTi) significantly protected against senescence and epithelial-to-mesenchymal transition in TGFβ-stimulated TECs.

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NNMT overexpression promotes tubular senescence and fibrosis in human chronic kidney disease (NAM and SAM supplementation in TEC cells) [Series_2]

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2025-11-20 | GSE280551 | GEO

Cyclin B1 deficiency in renal tubular epithelial cells promotes kidney ageing and fibrosis in mice

Project description:After severe renal injury, renal tubular epithelial cells (TECs) will be arrested in G2/M phase, and the arrested cells will be aging, showing senescence related secretory phenotype (SASP), which mediates renal fibrosis by secreting fibrogenic cytokines. Cyclin B1 is an important protein that promotes G2/M phase transition of cell cycle. Its role in renal fibrosis mediated by G2/M arrest of TECs is unknown. The aim of this study was to investigate the role of cyclin B1 in renal fibrosis induced by TECs G2/M arrest and its mechanism

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H3K9me3, H3K27me3, H3K27ac and H3K4me3 ChIP-sequencing in SUM159PT NNMT-WT, NNMT-KOd and NNMT KOs breast cancer cells.

Project description:The cellular heterogeneity within a tumor can be determined by core genetic and epigenetic programs that operate in certain cells (tumor initiating cells – TICs), providing them with the degree of plasticity needed for induction of metastasis and resistance to therapy. Here we show that the metabolic enzyme nicotinamide N-methyl transferase (NNMT) promotes TIC plasticity in Estrogen Receptor (ER) alpha negative breast cancer. NNMT downregulation delays tumor formation and its full depletion impairs metastasis formation in mice. Mechanistically, NNMT loss increases deposition of H3K9-me2/3 and H3K27-me3 at the promoter of genes involved in stem cell regulation, shutting down their expression and upregulating luminal differentiation genes. This study reveals a major function of NNMT in maintaining core epigenetic programmes that promote TIC self-renewal and metastasis and that repress luminal differentiation.

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Sirtuin 3 regulates mitochondrial protein acetylation and metabolism in tubular epithelial cells during renal fibrosis

Project description:Proximal tubular epithelial cells (TECs) demand high energy and rely on mitochondrial oxidative phosphorylation as a main energy source. However, this is disturbed in renal fibrosis. Acetylation is an important posttranslational modification for mitochondrial metabolism. The mitochondrial protein NAD-dependent deacetylase sirtuin 3 (SIRT3) regulates mitochondrial metabolic function. Therefore, we aimed to identify the changes in the acetylome in tubules from fibrotic kidneys and determine their association with mitochondria. We found that decreased SIRT3 expression was accompanied by increased acetylation in mitochondria that have separated from TECs during the early phase of renal fibrosis. SIRT3 knockout mice were susceptible to hyper-acetylated mitochondrial proteins and to severe renal fibrosis. The activation of SIRT3 by honokiol ameliorated acetylation and prevented renal fibrosis. Analysis of the acetylome in separated tubules using LC-MS/MS showed that most kidney proteins were hyper-acetylated after unilateral ureteral obstruction. The increased acetylated proteins with 26.76% were mitochondrial proteins which were mapped to a broad range of mitochondrial pathways including fatty acid β-oxidation, the TCA cycle and oxidative phosphorylation. Pyruvate dehydrogenase E1α (PDHE1α), which is the primary link between glycolysis and the TCA cycle, was hyper-acetylated at lysine 385 in TECs after TGF-β1 stimulation, and was regulated by SIRT3. Our findings showed that mitochondrial proteins involved in regulating energy metabolism were acetylated and targeted by SIRT3 in TECs. The deacetylation of PDHE1α by SIRT3 at lysine 385 plays a key role in metabolic reprogramming associated with renal fibrosis.

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Microarray analysis of NNMT overexpression and knockdown in stromal cells

Project description:Analysis of gene expression in human CAFs with control (shCtrl) or shRNA against NNMT (shNNMT) expression or normal fibroblasts expressing control (Ctrl) or NNMT overexpression (NNMT) constructs. Cells were infected with lentivirus to express the indicated shRNA construct. Hypothesis is that knockdown of NNMT will affect expression of genes via regulation of histone methylation status.

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NNMT inhibition in cancer-associated fibroblasts restores antitumor immunity.

Project description:Cancer-associated fibroblasts (CAFs) play a pivotal cancer-supportive role, yet CAF-targeted therapies remain elusive. Through spatial transcriptomics and single-cell RNA sequencing, we investigated the role of nicotinamide N-methyltransferase (NNMT) in high-grade serous ovarian cancer (HGSOC). Mechanistically, NNMT-induced H3K27me3 hypomethylation drives complement secretion from CAFs, attracting immunosuppressive myeloid-derived suppressor cells (MDSCs) to the tumor. NNMT knockout in immunocompetent mice impaired tumor growth in syngeneic ovarian, breast, and colon tumor models through enhanced CD8+ T cell activation. Using high-throughput screening, we developed a potent and specific NNMT inhibitor that reduces tumor burden and metastasis in multiple murine cancer models and restores immune checkpoint blockade efficacy by decreasing CAF-mediated MDSC recruitment and reinvigorating CD8⁺ T cell activation. Our findings establish NNMT as a central CAF regulator and promising therapeutic target to mitigate immunosuppression in the tumor microenvironment.

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| PRJNA472964 | ENA

NNMT inhibition in cancer-associated fibroblasts restores antitumor immunity

Project description:Cancer-associated fibroblasts (CAFs) play a pivotal cancer-supportive role, yet CAF-targeted therapies remain elusive. Through spatial transcriptomics and single-cell RNA sequencing, we identified nicotinamide N-methyltransferase (NNMT) as a central CAF regulator in high-grade serous ovarian cancer (HGSOC) patients. Mechanistically, NNMT-induced H3K27me3 hypomethylation drives complement secretion from CAFs, attracting immunosuppressive myeloid-derived suppressor cells (MDSCs) to the tumor. Using high-throughput screening, we developed a potent, specific NNMT inhibitor that reduces tumor burden in multiple murine cancer models and restores immune checkpoint blockade efficacy by decreasing CAF-mediated MDSC recruitment and reinvigorating CD8⁺ T cell activation. Our findings establish NNMT as an essential CAF regulator and promising therapeutic target to mitigate immunosuppression in the tumor microenvironment.

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