SGLT2 inhibitors may offer benefit beyond diabetes

Kang, Amy; Jardine, Meg

doi:10.1038/s41581-020-00391-2

Cited by 34 publications

(37 citation statements)

References 10 publications

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“…Lipid accumulation and mitochondrial dysfunction also negatively affect the heart 18 . The anti-hyperglycaemic sodium-glucose cotransporter 2 (SGLT2) inhibitors improve both renal and cardio vascular outcomes in patients with CKD with and without diabetes 186 , and these protective effects seem to involve restoration of mitochondrial function, increased autophagic flux and reduced cellular stress, among others 187 . Vascular dysfunction is a hallmark of both CVD and CKD 20 , and ongoing clinical studies will assess how targeting mitochondrial function and oxidative stress directly in patients with CKD affects microvascular and endothelial function, inflammatory and oxidative stress markers [188][189][190] .…”

Section: Discussionmentioning

confidence: 99%

Lipoproteins and fatty acids in chronic kidney disease: molecular and metabolic alterations

et al. 2021

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Section: Discussionmentioning

confidence: 99%

Lipoproteins and fatty acids in chronic kidney disease: molecular and metabolic alterations

et al. 2021

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“…SGLT2i may act on systemic and cardiac insulin resistance, as evidenced by the observation that both HOMA-IR and cardiomyocyte insulin receptor levels were improved by SGLT2i therapy. SGLT2i influence cardiac energy metabolism, breaking the vicious circle between HF and IR and mediating cardioprotective effects by regulating mitochondrial function, modulating glucose metabolism, enhancing fatty acid metabolism, and shifting to ketone body metabolism [20,21]. Therefore, SGLT2i can increase glucose and fatty acid utilization and shift the myocardial fuel from glucose to ketone bodies and free fatty acids.…”

Section: Discussionmentioning

confidence: 99%

Sodium/glucose cotransporter 2 (SGLT2) inhibitors improve cardiac function by reducing JunD expression in human diabetic hearts

et al. 2022

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“…In the kidney, the proximal tubule is the primary site for glucose metabolism and plays a dual role in glucose reabsorption and gluconeogenesis (6). Sodium glucose cotransporter 2 inhibitors (SGLT2i) block glucose reabsorption in the proximal tubule and slow progression of DKD (7). SGLT2i may have benefits that extend beyond glycemic control, which has renewed interest in finding additional therapeutic targets in the kidney (7).…”

Section: Introductionmentioning

confidence: 99%

“…Sodium glucose cotransporter 2 inhibitors (SGLT2i) block glucose reabsorption in the proximal tubule and slow progression of DKD (7). SGLT2i may have benefits that extend beyond glycemic control, which has renewed interest in finding additional therapeutic targets in the kidney (7).…”

Section: Introductionmentioning

confidence: 99%

Multimodal single cell sequencing of human diabetic kidney disease implicates chromatin accessibility and genetic background in disease progression

Wilson

Karihaloo

et al. 2022

Preprint

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Multimodal single cell sequencing is a powerful tool for interrogating cell-specific changes in transcription and chromatin accessibility. We performed single nucleus RNA (snRNA-seq) and assay for transposase accessible chromatin sequencing (snATAC-seq) on human kidney cortex from donors with and without diabetic kidney disease (DKD) to identify altered signaling pathways and transcription factors associated with DKD. Both snRNA-seq and snATAC-seq had an increased proportion of VCAM1+ injured proximal tubule cells (PT_VCAM1) in DKD samples. PT_VCAM1 has a pro-inflammatory expression signature and transcription factor motif enrichment implicated NFkB signaling. We used stratified linkage disequilibrium score regression to partition heritability of kidney-function-related traits using publicly-available GWAS summary statistics. Cell-specific PT_VCAM1 peaks were enriched for heritability of chronic kidney disease (CKD), suggesting that genetic background may regulate chromatin accessibility and DKD progression. snATAC-seq found cell-specific differentially accessible regions (DAR) throughout the nephron that change accessibility in DKD and these regions were enriched for glucocorticoid receptor (GR) motifs. Changes in chromatin accessibility were associated with decreased expression of insulin receptor, increased gluconeogenesis, and decreased expression of the GR cytosolic chaperone, FKBP5, in the diabetic proximal tubule. Cleavage under targets and release using nuclease (CUT&RUN) profiling of GR binding in bulk kidney cortex and an in vitro model of the proximal tubule (RPTEC) showed that DAR co-localize with GR binding sites. CRISPRi silencing of GR response elements (GRE) in the FKBP5 gene body reduced FKBP5 expression in RPTEC, suggesting that reduced FKBP5 chromatin accessibility in DKD may alter cellular response to GR. We developed an open-source tool for single cell allele specific analysis (SALSA) to model the effect of genetic background on gene expression. Heterozygous germline single nucleotide variants (SNV) in proximal tubule ATAC peaks were associated with allele-specific chromatin accessibility and differential expression of target genes within cis-coaccessibility networks. Partitioned heritability of proximal tubule ATAC peaks with a predicted allele-specific effect was enriched for eGFR, suggesting that genetic background may modify DKD progression in a cell-specific manner.

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SGLT2 inhibitors may offer benefit beyond diabetes

Cited by 34 publications

References 10 publications

Lipoproteins and fatty acids in chronic kidney disease: molecular and metabolic alterations

Lipoproteins and fatty acids in chronic kidney disease: molecular and metabolic alterations

Sodium/glucose cotransporter 2 (SGLT2) inhibitors improve cardiac function by reducing JunD expression in human diabetic hearts

Multimodal single cell sequencing of human diabetic kidney disease implicates chromatin accessibility and genetic background in disease progression

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