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Dapagliflozin alleviates renal inflammation and protects against diabetic kidney diseases dependent and independent of glucose levels [RNA-seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE246576 | GEO | 2023/11/02

REPOSITORIES: GEO

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Dapagliflozin alleviates renal inflammation and protects against diabetic kidney diseases dependent and independent of glucose levels [ATAC-seq]

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

Proximal tubular epithelial specific transcriptomics of diabetic mice treated with dapagliflozin

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Dapagliflozin alleviates diabetic kidney disease via HIF1α/HO1 mediated ferroptosis

Project description:To investigate the mechanism of the renal protective effects of SGLT2i in diabetic nephropathy, we treated 9-week db/db mice with dapagliflozin and solvent, respectively. This study used m/m mice as control group.We performed gene expression profiling analysis using data obtained from RNA-seq of 3 different groups of mice after 13-week treatment.

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Project description:Diabetic kidney disease (DKD) appears heritable, suggesting genetic factors influence disease susceptibility. In our study, genes were mapped mediating early renal hypertrophic in response to diabetes. A survey of murine strains (N=15) was conducted to identify variation in kidney hypertrophy following diabetes induction. Mice with greater FVB/N and less C57BL/6 renal hypertrophy were crossed and diabetic F2 generation mice (n=534) were characterised. To confirm loci responsible for the renal hypertrophic response, diabetic congenic mice were generated by backcrossing FVB/N mice that conferred greater or C57BL/6 conferring lower risk into the reciprocal strain mice. Kidney weights of (FVB/N x C57BL/6) F2 diabetic mice were broadly distributed. Quantitative trait locus (QTL) analysis revealed that diabetic mice with kidney weights in the upper quartile shared alleles on chromosomes 6 and 12, with the FVB/N allele on chromosome 6 conferring greater susceptibility. On chromosome 12, C57BL/6 homozygotes were more significantly represented (LOD=3.8) conferring less susceptibility. The diabetic B6.Drc1/2f congenic strain developed kidney damage, while the reciprocal congenic, with FVB.Drc1/2b strain were protected. Microarray analysis identified differentially expressed genes between diabetic C57BL/6 and FVB/N mice. QTL mapping for early renal responses to diabetes identified two loci syntenic with regions identified for human diabetic kidney disease. Providing a new resource to study DKD.

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RNAs sequencing revealing the gene expression profiling in kidney tissues between diabetic kidney disease and control

Project description:Diabetic kidney disease (DKD), a progressive kidney disease, is a major complication associated with diabetes and has become the leading cause of chronic kidney disease in China. Increasing evidences have demonstrated that lncRNAs play vital roles in kidney diseases, including DKD. To search for new ncRNAs involved in DKD, we performed gene expression profiling in the kidney tissues isolated from DKD patients and non-diabetic renal cancer patients undergoing surgical resection by RNA sequencing. And we identified 65 DEncRNAs (29 upregulated and 36 downregulated in DKD) and 171 DEmRNAs (72 upregulated and 99 downregulated in DKD).This study will provide insights into the prevent and treatment of DKD in the future.

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Project description:The pathogenesis of diabetic kidney disease (DKD) involves multifactorial processes that converge to initiate and advance the disease. Although DKD is not typically classified as an inflammatory glomerular disease, mounting evidence supports the involvement of renal inflammation as a key contributor in DKD pathogenesis, particularly through macrophages. However, detailed identification and corresponding phenotypic changes in macrophages in DKD remain poorly understood. To capture the gene expression changes in specific macrophage cell subsets in early DKD, we performed a single-cell transcriptomic analysis of CD45-enriched kidney immune cells from type 1 diabetic OVE26 mice at two time points during the disease development and undertook a focused analysis of mononuclear phagocytes (i.e., macrophages and dendritic cells). Our results now show increased resident and infiltrating macrophage subsets in the diabetic kidneys over time, with heightened expression of pro-inflammatory or anti-inflammatory genes in a subset-specific manner. Further analysis of macrophage polarization states in each subset showed changes consistent with the continuum of activation and differentiation states, and their gene expression tended to shift toward undifferentiated phenotypes but with increased M1-like inflammatory phenotypes over time and in the diabetic kidneys. By deconvolution analysis of RNAseq samples of human DKD biopsies and immunostaining, we further confirmed a differential expression of select genes in specific macrophage subsets. Thus, the current study provides a comprehensive analysis of macrophage transcriptomic profiles in early DKD that underscores the dynamic macrophage phenotypes in disease progression.

2022-11-08 | GSE195799 | GEO

Connectivity mapping of glomerular proteins identifies dimethylaminoparthenolide as a new inhibitor of diabetic kidney disease

Project description:While blocking the renin angiotensin aldosterone system (RAAS) has been the main therapeutic strategy to control diabetic kidney disease (DKD) for many years, 25-30% of diabetic patients still develop the disease. In the present work we adopted a system biology strategy to analyze glomerular protein signatures to identify drugs with potential therapeutic properties in DKD acting through a RAAS-independent mechanism. Glomeruli were isolated from wild type and type 1 diabetic mice (Ins2Akita) treated or not with the angiotensin-converting enzyme inhibitor (ACEi) ramipril. Ramipril efficiently reduced the urinary albumin/creatine ratio (ACR) of Ins2Akita mice without modifying DKD-associated renal-injuries. Large scale quantitative proteomics was used to identify the DKD-associated glomerular proteins (DKD-GPs) that were ramipril-insensitive (RI-DKD-GPs). We then applied an in silico drug repurposing approach using a pattern-matching algorithm (Connectivity Mapping) to compare the RI-DKD-GPs’s signature with a collection of thousands of transcriptional signatures of bioactive compounds. The sesquiterpene lactone parthelonide was identified as one of the top compounds predicted to reverse the RI-DKD-GPs’s signature. Treatment of diabetic Ins2Akita mice with dimethylaminoparthenolide (DMAPT), a water soluble analogue of parthenolide, significantly reduced urinary ACR. However, in contrast to ramipril, DMAPT also significantly reduced glomerulosclerosis and tubulointerstitial fibrosis. Using a system biology approach we identified DMAPT, as a compound with a potential add-on value to standard-of-care ACEi-treatment in DKD.

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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

Dapagliflozin ameliorates diabetes-induced spermatogenic dysfunction by modulating the adenosine metabolism along the gut microbiota-testis axis

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.

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Transcriptome Analysis of Human Diabetic Kidney Disease

Project description:This SuperSeries is composed of the following subset Series: GSE30528: Transcriptome Analysis of Human Diabetic Kidney Disease (DKD Glomeruli vs. Control Glomeruli) GSE30529: Transcriptome Analysis of Human Diabetic Kidney Disease (DKD Tubuli vs. Control Tubuli) GSE30566: Transcriptome Analysis of Human Diabetic Kidney Disease (Control Glomeruli vs. Control Tubuli) Refer to individual Series

2011-08-02 | E-GEOD-30122 | biostudies-arrayexpress

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