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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

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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.

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