Transcription factor c-Maf deletion improves streptozotocin-induced diabetic nephropathy by directly regulating Sglt2 and Glut2
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ABSTRACT:
PROVIDER: PRJNA822075 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18579290_1.fastq.gz | Fastqsanger.gz | |||
| SRR18579290_2.fastq.gz | Fastqsanger.gz | |||
| SRR18579291_1.fastq.gz | Fastqsanger.gz | |||
| SRR18579291_2.fastq.gz | Fastqsanger.gz | |||
| SRR18579292_1.fastq.gz | Fastqsanger.gz |
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Project description:The transcription factor c-Maf has been widely studied and has been reported to play a critical role in embryonic kidney development; however, the postnatal functions of c-Maf in adult kidneys remain unknown as c-Maf null C57BL/6J mice exhibit embryonic lethality. In this study, we investigated the role of c-Maf in adult mouse kidneys by comparing the phenotypes of tamoxifen (TAM)-inducible c-Maf knockout mice (c-Maf flox/flox; CAG-Cre-ERTM mice named “c-Maf ΔTAM”) with that of c-Maf flox/flox control mice, 10 days after TAM injection (TAM(10d)). In addition, we examined the effects of c-Maf deletion on diabetic conditions by injecting the mice with streptozotocin (STZ), 4 weeks before TAM injection. c-Maf ΔTAM mice displayed primary glycosuria caused by Sglt2 and Glut2 downregulation in the kidneys without diabetes, as well as morphological changes and life-threatening injuries in the kidneys on TAM(10d). Under diabetic conditions, c-Maf deletion promoted recovery from hyperglycemia and suppressed albuminuria and diabetic nephropathy by causing similar effects as did Sglt2 knockout and SGLT2 inhibitors. In addition to demonstrating the unique gene regulation of c-Maf, these findings highlight the renoprotective effects of c-Maf deficiency under diabetic conditions and suggest that c-Maf could be a novel therapeutic target gene for treating diabetic nephropathy.
2023-02-01 | GSE199916 | GEO
Project description:diabetes, mouse models, diabetic nephropathy, streptozotocin db/db Keywords: other
2004-01-20 | GSE710 | GEO
Project description:The transcription factor c-Maf has been widely studied and has been reported to play a critical role in embryonic kidney development; however, the postnatal functions of c-Maf in adult kidneys remain unknown as c-Maf-null C57BL/6J mice exhibit embryonic lethality. In this study, we investigated the role of c-Maf in adult mouse kidneys by comparing the phenotypes of tamoxifen-inducible (TAM-inducible) c-Maf-knockout mice (c-Maffl/fl; CAG-Cre-ERTM mice named "c-MafΔTAM") with those of c-Maffl/fl control mice, 10 days after TAM injection [TAM(10d)]. In addition, we examined the effects of c-Maf deletion on diabetic conditions by injecting the mice with streptozotocin, 4 weeks before TAM injection. c-MafΔTAM mice displayed primary glycosuria caused by sodium-glucose cotransporter 2 (Sglt2) and glucose transporter 2 (Glut2) downregulation in the kidneys without diabetes, as well as morphological changes and life-threatening injuries in the kidneys on TAM(10d). Under diabetic conditions, c-Maf deletion promoted recovery from hyperglycemia and suppressed albuminuria and diabetic nephropathy by causing similar effects as did Sglt2 knockout and SGLT2 inhibitors. In addition to demonstrating the potentially unique gene regulation of c-Maf, these findings highlight the renoprotective effects of c-Maf deficiency under diabetic conditions and suggest that c-Maf could be a novel therapeutic target gene for treating diabetic nephropathy.
| S-EPMC10070115 | biostudies-literature
Project description:Streptozotocin (STZ) is an anti-cancer drug that is primarily used to treat neuroendocrine tumors (NETs) in clinical settings and develop type 1 diabetes rodent models in experimental fields. STZ is incorporated into cells through the glucose transporter, GLUT2, which is primarily expressed in pancreatic β-cells or proximal tubular epithelial cells in the kidney. However, its cytotoxic effects on kidney cells have been underestimated and the underlying mechanisms remain unclear. We herein demonstrated that DNA damage and subsequent p53 signaling were responsible for the development of STZ-induced tubular epithelial injury. We detected tubular epithelial DNA damage in NET patients treated with STZ. Unbiased transcriptomics of tubular epithelial cells in vitro showed the activation of the p53 signaling pathway by STZ. STZ induced DNA damage and activated p53 signaling in vivo in a dose-dependent manner, resulting in reduced membrane transport. The localization of STZ-induced kidney injury was limited to within the kidney cortex, which was independent of blood glucose. The pharmacological inhibition of p53 and sodium-glucose transporter 2 (SGLT2) mitigated STZ-induced epithelial injury. However, the cytotoxic effects of STZ on pancreatic β-cells were preserved in SGLT2 inhibitor-treated mice. The present results demonstrate the strong proximal tubular-specific cytotoxicity of STZ and the underlying mechanisms in vivo, which may be ameliorated by a SGLT2 inhibitor pretreatment. Since the cytotoxic effects of STZ against β-cells were not impaired by dapagliflozin, a pretreatment with a SGLT2 inhibitor has potential as a preventative remedy for kidney injury in NET patients treated with STZ.
2023-06-07 | GSE215337 | GEO
Project description:Purpose:Renal injury with the loss of podocyte was characteristic pathology of diabetic nephropathy (DN) and correlated with increased albuminuria. Many studies have found the nephroprotective effect of the novel inhibitors of sodium-glucose cotransporter 2 (SGLT2-is), like Dapagliflozin, delaying the progression of DN. However, the underlying mechanisms of SGLT2 associated with podocyte injury are still not fully elucidated. Methods: Through mRNA sequencing, streptozotocin-induced and Dapagliflozin-intraperitoneal injection mice models were established to explore potential mechanism between Dapagliflozin and renal phenotype. And all changes referring this observed pathway were proven repeatedly in podocyte. Results: Here, we generated the streptozotocin-induced DN models and found the accumulation of nephrotoxin and pathological lesions of the kidney, including interstitial inflammatory infiltration, mesangial expansion and glomerular sclerosis, while low expression of SGLT2 mitigated these injuries in Dapagliflozin-treated mice. Moreover, mRNA expression profile in these treated models determined the significance of insulin-like growth factor-1 receptor (IGF1R)/PI3K regulatory axis in glomerular injury. Particularly, SGLT2-is inhibited the increase of mesenchymal marker, α-SMA and the decrease of podocyte marker, nephrin at the gene or protein level. KEGG analysis also showed the enrichment of phosphatidylinositol signaling system and TGF-β/smad pathway. In parallel, the protein level of IGF1R, phosphorylated PI3K, and α-SMA were increased in high-glucose stimulated human podocyte, and reduced in Dapagliflozin (50nM and 100nM) or OSI-906 (inhibitor of IGF1R, 60nM) used groups. Notably, combination of the two inhibitors produced an accumulative effect in the protection of podocyte integrity. Mechanistically, IGF1 or IGF2 could bind to IGF1 receptors to mediate the epithelial-mesenchymal transition (EMT) of diabetic podocyte in response to the upregulation of SGLT2. Indeed, we enrolled the urine and plasma samples from a cohort consisting of 13 healthy people, and a cohort of 19 patients with DN using SGLT2-inhibitors (n=9) or not (n=10). Compared with pure DN patients, Elisa results suggested an increased circulation and excretion level of IGF1/2 in SGLT2-is used DN cohort. Conclusions: Taken together, our study reported the key role of SGLT2/IGF1R/PI3K signaling in regulating podocyte EMT. Modulating the IGF1R expression may provide a novel idea for DN therapy.
2022-10-19 | GSE200322 | GEO
Project description:Hypertensive nephropathy is a common complication of hypertension that places a heavy burden on society. SGLT2 inhibitors are a new class of hypoglycemic agents that have been shown to have specific protective effects on the kidneys. This study aimed to investigate the early changes in renal transcription spectrum in spontaneously hypertensive rats and the effects of DAPA, a sodium-glucose cotransporter 2 inhibitor, on the remission of hypertensive nephropathy and its underlying molecular mechanisms. We furthermore show thatSGLT2 inhibitors may reduce inflammation and improve energy metabolism by regulating the expression of SLC9a3, Zbtb20, Trim50 and Ccnl2.
2024-06-30 | GSE207191 | GEO
Project description:Glucose transporter 2 (GLUT2) is a key player in the regulation of glucose dynamics in organs central to metabolism, namely the liver, pancreas and intestine In humans, mutations of the GLUT2 gene (Fanconi-Bickel syndrome) cause important defects in glucose homeostasis. Although GLUT2 has been studied in the context of its participation in peripheral and central glucose sensing, to date it is still unclear which role it plays in the brain. In this regard, in order to shed some light on the function of GLUT2 in the vertebrate brain, we have knocked down the functional ortholog of human GLUT2 in zebrafish. Our results show that abrogation of glut2 in vivo leads to defective brain organogenesis coinciding with reduced glucose uptake and increased programmed cell death in the brain region. Interestingly, coinciding with the observed localization of glut2 expression in the hindbrain, glut2 deficiency affected the development of neural progenitor cells expressing the proneural genes atoh1b and ptf1a that are the source of glutamatergic and GABAergic neurons, respectively. In addition, progenitor cells expressing neurod, a marker for immature and mature granule cells, were not affected by the lack of glut2. Furthermore, transcriptome analysis of glut2 knockdown embryos supports the notion that the lack of glut2 impacts brain development. Overall, the results of this study highlight the physiological relevance of glut2 in glucose uptake and availability during brain development, supporting the important role of glut2 in brain glucose sensing, and demonstrate the usefulness of a novel in vivo model of GLUT2 deficiency. Control and ATG morphant embryos were harvested at 72 hpf and RNA samples were obtained from pools of 20 embryos per condition and three pooled biological replicates of control and ATG morphants were analyzed.
2014-12-23 | E-GEOD-57836 | biostudies-arrayexpress
Project description:Glucose transporter 2 (GLUT2) is a key player in the regulation of glucose dynamics in organs central to metabolism, namely the liver, pancreas and intestine In humans, mutations of the GLUT2 gene (Fanconi-Bickel syndrome) cause important defects in glucose homeostasis. Although GLUT2 has been studied in the context of its participation in peripheral and central glucose sensing, to date it is still unclear which role it plays in the brain. In this regard, in order to shed some light on the function of GLUT2 in the vertebrate brain, we have knocked down the functional ortholog of human GLUT2 in zebrafish. Our results show that abrogation of glut2 in vivo leads to defective brain organogenesis coinciding with reduced glucose uptake and increased programmed cell death in the brain region. Interestingly, coinciding with the observed localization of glut2 expression in the hindbrain, glut2 deficiency affected the development of neural progenitor cells expressing the proneural genes atoh1b and ptf1a that are the source of glutamatergic and GABAergic neurons, respectively. In addition, progenitor cells expressing neurod, a marker for immature and mature granule cells, were not affected by the lack of glut2. Furthermore, transcriptome analysis of glut2 knockdown embryos supports the notion that the lack of glut2 impacts brain development. Overall, the results of this study highlight the physiological relevance of glut2 in glucose uptake and availability during brain development, supporting the important role of glut2 in brain glucose sensing, and demonstrate the usefulness of a novel in vivo model of GLUT2 deficiency.
2014-12-23 | GSE57836 | GEO
Project description:The CANVAS program revealed that the SGLT2 inhibitor canagliflozin increases the risk for lower-limb (minor) amputations in type 2 diabetics about a two-fold. On the contrary, the large RCTs with empagliflozin and dapagliflozin did not demonstrate a similar observation. Thus, a question arises whether the increased risk for minor amputations is associated only with canagliflozin or whether it is a class effect of SGLT2 inhibitors. Vascular disorders including defective angiogenesis are among the leading causes of lower-limb amputations. Therefore, here we examined the effects of empagliflozin, dapagliflozin, and canagliflozin on angiogenesis using zebrafish embryos and HUVECs.
2022-12-31 | GSE191046 | GEO
Project description:SGLT2 inhibitors and zebrafish
| PRJNA789531 | ENA