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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

The single-cell landscape reveals kidney immune cell transcriptional heterogeneity in early diabetic kidney disease

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 an inflammatory glomerular disease, mounting evidence supports the involvement of renal inflammation as a key contributor in DKD pathogenesis. However, detailed characteristics of specific immune cell types in the context of diabetic kidneys remain poorly understood. To capture the gene expression changes in specific immune cell subsets in early DKD, we performed a single-cell transcriptomic analysis of CD45-enriched kidney immune cells from control and diabetic OVE26 mice. Unsupervised clustering identified 11 distinct cell types that represented the major immune cells and an unidentified cell type. Further analysis of mononuclear phagocytes showed increased macrophage subsets in the diabetic kidneys and that pro-inflammatory and anti-inflammatory macrophages were concomitantly increased. Moreover, rather than in discrete M1 or M2 states, many macrophage subsets expressed genes consistent with the continuum of activation and differentiation states, and that their gene expression shifted toward increased inflammatory and differentiated status in the diabetic kidneys. Our study provides a comprehensive analysis of immune cell transcriptomic profiles in mouse DKD and underscores the dynamic macrophage activation in promoting DKD.

2022-11-08 | GSE195799 | GEO

Analysis of renal protective effects of ARB and SGLT2i at single cell level.

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

Proximal tubular epithelial specific transcriptomics of diabetic mice treated with dapagliflozin

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

Genetic characerization of early renal changes in diabetes

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.

2021-12-31 | GSE123677 | GEO

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.

2023-02-22 | GSE199838 | GEO

Puerarin attenuates diabetic kidney injury through interaction with Guanidine nucleotide-binding protein Gi subunit alpha-1 (Gnai1) subunit

Project description:Radix puerariae, a traditional Chinese herbal medication, has been used to treat patients with diabetic kidney disease (DKD). Our previous studies demonstrated that puerarin, the active compound of radix puerariae, improves diabetic podocyte injury in type 1 DKD mice through attenuation of oxidative stress. However, the direct molecular target of puerarin and its underlined mechanisms in DKD remains unknown. In this study, we first confirmed that puerarin also improved DKD in type 2 diabetic mice (db/db). Through RNA-sequencing of isolated glomeruli, we found that differentially expressed genes (DEGs) that were altered in the glomeruli of these diabetic mice but reversed by puerarin treatment were involved mostly in oxidative stress, inflammatory, and fibrosis. Further analysis of these reversed DEGs revealed protein kinase A (PKA) was among the top pathways. By utilizing the drug affinity responsive target stability (DARTS) method combined with mass spectrometry analysis we identified guanine nucleotide-binding protein Gi alpha-1 (Gnai1) as the direct binding partner of puerarin. Gnai1 is an inhibitor of cAMP production which is known to have protection against podocyte injury. Searching Nephroseq datasets revealed that Gnai1 expression increased in the glomeruli of human DKD. In vitro, we showed that puerarin not only interacted with Gnai1 but also increased cAMP production in human podocytes and kidney cortex of mice treated with peurarin. Puerarin also enhanced CREB phosphorylation, a downstream transcription factor of cAMP/PKA. Overexpression of CREB reduced high glucose-induced podocyte apoptosis. We conclude that the renal protective effects of puerarin are likely through inhibiting Gnai1 to activate cAMP/PKA/CREB pathway in podocytes.

2022-02-15 | GSE196780 | GEO

Targeting methylglyoxal in diabetic kidney disease using the novel mitochondria-targeted compound MitoGamide

Project description:Diabetic kidney disease (DKD) remains the number one cause of end-stage renal disease in the western world. Currently there is no treatment to cure diabetes or deal effectively with its complications. In experimental diabetes, mitochondrial dysfunction in the kidney has been widely reported with changes in mitochondrial bioenergetics preceding the development of the renal lesion. Glucose-derived molecules generated during diabetes, known as dicarbonyls, such as methylglyoxal, are thought to impair mitochondrial function and may contribute to the pathogenesis of DKD. Here, we sought to target methylglyoxal within the mitochondria using MitoGamide, the novel mitochondria-targeted dicarbonyl scavenger, in an experimental model of diabetes. Male 6-week-old heterozygous Akita mice (C57BL/6-Ins2-Akita/J) or wildtype littermates were randomized to receive MitoGamide (10mg/kg/day) or vehicle by oral gavage for 16 weeks. MitoGamide did not alter blood glucose control or body composition. Akita mice exhibited hallmarks of DKD including albuminuria, hyperfiltration, glomerulosclerosis and renal fibrosis, however, after 16 weeks of treatment, MitoGamide did not substantially improve the renal phenotype. Complex-I-linked mitochondrial respiration was increased in the kidney of Akita mice which was unaffected by MitoGamide. Exploratory studies using transcriptomics identified that MitoGamide induced changes to olfactory signalling, immune system, respiratory electron transport and post-translational protein modification pathways. These findings indicate that targeting methylglyoxal within the mitochondria using MitoGamide is not a valid therapeutic approach for DKD and that other mitochondrial targets or processes upstream should be the focus of therapy.

2020-10-23 | GSE159882 | 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.

2020-09-17 | PXD018728 | Pride

Arctigenin attenuates diabetic kidney disease through the activation of PP2A in podocytes

Project description:Arctigenin (ATG) is a major component of Fructus Arctii, which as a traditional herbal remedy reduced proteinuria in diabetic patients. However, whether ATG specifically provided renoprotection in DKD was not known. Here we report that ATG administration is sufficient to attenuate proteinuria and podocyte injury in mouse models of diabetes. Transcriptomic analysis of diabetic mouse glomeruli showed that cell adhesion and inflammation are two key pathways affected by ATG treatment, and mass spectrometry analysis identified protein phosphatase 2A (PP2A) as one of the top ATG-interacting proteins in renal cells. Enhanced PP2A activity by ATG reduces p65 NF-κB-mediated inflammatory response and high glucose-induced migration in cultured podocytes via its interaction with Drebrin-1. Importantly, podocyte-specific Pp2a deletion in mice exacerbates DKD injury and abrogates the ATG-mediated renoprotection. Collectively, our results clearly demonstrate a renoprotective mechanism of ATG via PP2A activation and establish PP2A as a potential target for DKD progression.

2019-11-08 | PXD014976 | Pride

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