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Dapagliflozin alleviates renal inflammation and protects against diabetic kidney diseases dependent and independent of glucose levels

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE246826 | GEO | 2023/11/02

REPOSITORIES: GEO

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Dapagliflozin alleviates renal inflammation and protects against diabetic kidney diseases, both dependent and independent of blood glucose levels.

Project description: Not available

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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.

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

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

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

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Inhibition of Hippo signaling pathway preserves renal mitochondrial quality control homeostasis and protects against diabetic kidney diseases

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 are highly warranted. Here, we analyzed renal cortex from healthy mice, diabetic mice, and diabetic mice treated with the Hippo signaling pathway inhibitor XMU-MP-1. Our study first confirmed that XMU-MP-1 improved DKD in type 2 diabetic mice induced by high-fat diet feeding and intraperitoneal injection of streptozotocin. Through RNA-sequencing of isolated renal cortex, we found that activation of the Hippo signaling pathway, chemokine signaling pathway and cell activation involved in immune response were positively associated with the progression of DKD, while mitochondrion organization was negatively associated with the development of DKD. By contrast, administration of XMU-MP-1 partly suppressed the irritation of chemokine signaling pathway, and organ or tissue specific immune response, but preserved mitochondrion organization within renal cortex of DKD. In vitro, cell culture of immortalized renal tubule cells revealed that overexpression of yes-associated protein 1, the downstream core mediator of the Hippo signaling pathway, reduced high glucose and palmitic acid-induced tubule cell impairment by improving the maintenance of mitobiogenesis and mitophagy. Overall, our data emphasize that the renal protective effects of suppressing Hippo signaling pathway are likely through preserving the mitochondrial quality control homeostasis in tubule cells.

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