Dapagliflozin alleviates diabetic kidney disease via HIF1α/HO1 mediated ferroptosis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE228727 | GEO | 2023/05/31
REPOSITORIES: GEO
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Project description:We show the proximal tubular specific pathway analysis demonstrating the downregulation of oxidative phosphorylation in dapagliflozin treated db/db mice, a type 2 diabetic model. After 8-week treatment of dapagliflozin for db/db mice having proximal tubule specific tdTomato reporter, tdTomato-positive cells were isolated by FACS. Pathway analysis of RNA sequence of isolated tubular epithelia revealed that oxidative phosphorylation was downregulated in dapagliflozin-treated mice. However, depletion of renal tissue ATP content in db/db mice was ameliorated by dapagliflozin administration. Pimonidazole staining demonstrated that renal cortical tissue hypoxia was noted in db/db mice, which was improved by dapagliflozin administration. These findings suggest that dapagliflozin can ameliorated the excessive oxygen and ATP consumption and subsequent tissue hypoxia in diabetic kidney, which may explain, in part, the responsible mechanisms of renoprotecitive effect by dapagliflozin.
2022-09-28 | GSE185801 | GEO
Project description:Male infertility is one of the most common complications of diabetes mellitus (DM). Dapagliflozin is widely used to manage the type II DM. This study aimed to assess the dapagliflozin’s effects on the spermatogenesis by administering either dapagliflozin (Dapa) or a vehicle (db) to diabetic male db/db mice, and using littermate male db/m mice as the control group (Con). We further performed the integrative analyses of the cecal shotgun metagenomics, cecal/plasmatic/testicular metabolomics, and testicular proteomics. We found that dapagliflozin treatment significantly alleviated the diabetes-induced spermatogenic dysfunction by improving sperm quality, including the sperm concentration and the sperm motility. The overall microbial composition was reshaped in Dapa mice and 13 species (such as Lachnospiraceae bacterium 3-1) were regarded as potential beneficial bacteria. Metabolites exhibited modified profiles, in which adenosine, cAMP, and 2’-deoxyinosine being notably altered in the cecum, plasma, and testis, respectively. Testicular protein expression patterns were similar between the Dapa and Con mice. In vivo results indicated that compared with db group, dapagliflozin treatment alleviated apoptosis and oxidative stress in testis tissues by down-regulating 2’-deoxyinosine. This was further validated by in vitro experiments using GC-2 cells. Our findings support the potential use of Dapa to prevent the diabetes-induced impaired sperm quality and to treat diabetic male infertility.
2024-01-04 | PXD034622 | Pride
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 at the early phase are highly warranted. Here, we analyzed kidneys from healthy mice, diabetic mice, and diabetic mice treated with the sodium-glucose cotransporter 2 inhibitor dapagliflozin. Our combined method of ATAC and RNA sequencing revealed Csf2rb, Btla, and Isg15 as the key candidate genes associated with hyperglycemia, azotemia, and albuminuria. Their protein levels were altered together with multiple other inflammatory cytokines in the diabetic kidney, which was alleviated by dapagliflozin treatment. Cell culture of immortalized renal tubular cells and macrophages unraveled that dapagliflozin could directly effect on these cells in vitro as an anti-inflammatory agent independent of glucose concentrations. We further proved that dapagliflozin attenuated ischemia/reperfusion-induced chronic kidney injury and renal inflammation in mice. Overall, our data emphasize the importance of inflammatory factors to the pathogenesis of DKD, and provide valuable mechanistic insights into the renoprotective role of dapagliflozin.
2023-11-02 | GSE246763 | GEO
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 at the early phase are highly warranted. Here, we analyzed kidneys from healthy mice, diabetic mice, and diabetic mice treated with the sodium-glucose cotransporter 2 inhibitor dapagliflozin. Our combined method of ATAC and RNA sequencing revealed Csf2rb, Btla, and Isg15 as the key candidate genes associated with hyperglycemia, azotemia, and albuminuria. Their protein levels were altered together with multiple other inflammatory cytokines in the diabetic kidney, which was alleviated by dapagliflozin treatment. Cell culture of immortalized renal tubular cells and macrophages unraveled that dapagliflozin could directly effect on these cells in vitro as an anti-inflammatory agent independent of glucose concentrations. We further proved that dapagliflozin attenuated ischemia/reperfusion-induced chronic kidney injury and renal inflammation in mice. Overall, our data emphasize the importance of inflammatory factors to the pathogenesis of DKD, and provide valuable mechanistic insights into the renoprotective role of dapagliflozin.
2023-11-02 | GSE246576 | GEO
Project description:The specific mechanism of sodium-glucose cotransporter 2 (SGLT2) inhibitor in heart failure (HF) needs to be elucidated. In this study, we use SGLT2 global knockout (SGLT2-KO) mice to assess the mechanism of SGLT2 inhibitor on HF. Dapagliflozin ameliorates both myocardial infarction (MI)-and transverse aortic constriction (TAC) -induced HF. Global SGLT2-deficiency doesn’t exert protection against adverse remodeling in both MI- and TAC-induced HF models. Dapagliflozin blurs MI- and TAC-induced HF phenotypes in SGLT2-KO mice. Dapagliflozin causes major changes in cardiac fibrosis and inflammation. Based on single-cell RNA sequencing dapagliflozin causes significant differences in the gene expression profile of macrophages and fibroblasts. Moreover, dapagliflozin directly inhibites macrophage inflammation, thereby suppressing cardiac fibroblasts activation. The cardio-protection of dapagliflozin is blurred in mice treated with a C-C chemokine receptor type 2 (CCR2) antagonist. Taken together the protective effects of dapagliflozin against HF are independent of SGLT2, macrophage inhibition is the main target of dapagliflozin against HF.
2023-11-14 | GSE247062 | GEO
Project description:Angiotensin receptor blockade (ARB) and sodium-glucose co-transporter 2 inhibitor (SGLT2i) have been used as the standard therapy for patients with diabetic kidney disease (DKD). However, how these two drugs possess additive renal protective effects remains unclear. Here, we conducted single cell RNA-sequencing to profile the kidney cell transcriptome of db/db mice treated with vehicle, ARB, SGLT2i, or both drugs and db/m mice. We identified 10 distinct clusters of kidney cells with predominant proximal tubular (PT) cells. We found that ARB has more anti-inflammatory and anti-fibrosis effects while SGLT2i affects more mitochondrial function. We also identified a new PT subcluster which was increased in DKD but reversed by treatments.This new subcluster was also confirmed by Immunostaining of mouse and human kidneys with DKD. Together, our study reveal kidney cell-specific gene signatures in response to ARB and SGLT2i and also identified a new PT subcluster which provides new insight into DKD.
2021-11-05 | GSE181382 | GEO
Project description:Aims: Heart failure with preserved ejection fraction (HFpEF) is a multifactorial disease that constitutes several distinct phenotypes, including a common cardiometabolic phenotype with obesity and type 2 diabetes mellitus. Treatment options for HFpEF are limited, and development of novel therapeutics is hindered by the paucity of suitable preclinical HFpEF models that recapitulate the complexity of human HFpEF. Metabolic drugs, like Glucagon Like Peptide Receptor Agonist (GLP-1RA) and Sodium Glucose Transporter 2 inhibitors (SGLT2i), have emerged as promising drugs to restore metabolic perturbations and may have value in the treatment of the cardiometabolic HFpEF phenotype. We aimed to develop a multifactorial HFpEF mouse model that closely resembles the cardiometabolic HFpEF phenotype, and evaluated the GLP-1 RA liraglutide and a SGLT2i dapagliflozin. Methods&Results: Aged (18-22 months old) female C57BL/6J mice were fed a standardized chow (CTRL) or high fat diet (HFD) for 12 weeks. After 8 weeks HFD, Angiotensin-II (ANGII), was administered for 4 weeks via osmotic mini-pumps. HFD+ANGII resulted in a cardiometabolic HFpEF phenotype, including obesity, impaired glucose handling and metabolic dysregulation with inflammation. The multiple-hit resulted in typical clinical HFpEF features, including cardiac hypertrophy and fibrosis with preserved fractional shortening but with impaired myocardial deformation, atrial enlargement lung congestion, and elevated blood pressures. Treatment with liraglutide attenuated the cardiometabolic dysregulation and improved cardiac function, with reduced cardiac hypertrophy, less myocardial fibrosis, and attenuation of atrial weight, natriuretic peptide levels, and lung congestion. Dapagliflozin treatment improved glucose handling, but had mild effects on the HFpEF phenotype. Conclusions: We developed a mouse model that recapitulates the human HFpEF disease, providing a novel opportunity to study disease pathogenesis and development of enhanced therapeutic approaches. We furthermore show that attenuation of cardiometabolic dysregulation may represent a novel therapeutic target for treatment of HFpEF.
2020-09-16 | GSE153923 | GEO
Project description:The purpose of this study was to investigate the effect of dapagliflozin (DAPA), a sodium-glucose cotransporter 2 inhibitor, on relieving cardiac hypertrophy and its potential molecular mechanism. Dapagliflozin activated the Plin5/PPARα signaling axis and exerts a protective effect against cardiac hypertrophy.
2021-09-01 | GSE183120 | GEO
Project description:Analysis of differential genes in myocardial hypertrophy mice treated with dapagliflozin
| PRJNA759225 | ENA
Project description:To investigate the differential expressed circRNAs, and even their biological functions in human proximal tubular epithelial (HK-2) cells induced by normal glucose, high levels of glucose and treatment of dapagliflozin, metformin and vildagliptin.
2022-04-05 | GSE179226 | GEO