RNA-Seq transcriptome analysis of renal tissue from spontaneously hypertensive rats revealed renal protective effects of dapagliflozin, an inhibitor of sodium-glucose cotransporter 2

Wei, Jiangjun; Tan, Fangyan; Long, Xianglin; Fang, Qinghua; Wang, Yao; Wang, Jing; He, Jianhua; Yuan, Xin; Du, Jianlin

doi:10.1016/j.ejps.2023.106531

Cited by 5 publications

(3 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Zbtb20 is the highest expressed ZBTB member (Supplemental Fig. S1A), with previous studies pointing to Zbtb20 dysregulation playing a role in hypertensive renal tissue although the exact mechanisms remain unclear (Wei et al, 2023).…”

Section: Atac-seq Reveals Distinct Clusters Of Dynamically Accessible...mentioning

confidence: 87%

Protein Kinase A Inhibition Epigenetically SilencesRen1

Smith,

Paxton,

Medrano

et al. 2023

Preprint

View full text Add to dashboard Cite

Rationale: Renin-expressing cells are myoendocrine cells crucial for survival which detect changes in blood pressure and release renin to maintain homeostasis. One of the pathways responsible for renin expression includes cAMP as a central factor. cAMP binds to subunits of protein kinase A (PKA), ultimately recruiting both CBP and p300. Binding to the cAMP-responsive element in the renin enhancer region thus amplifies renin transcription. Objective: To evaluate transcriptomic and epigenomic changes occurring at the renin locus via cAMP pathway inhibition. Methods and Results: We treated As4.1 cells (a tumoral cell line that constitutively expresses renin) with the PKA inhibitor H89 (treated) or DMSO (control). We then performed independent ATAC-seq, scRNA-seq, and ChIP-seq for H3K27Ac and P300 binding on biological replicates of treated and control As4.1 cells. Ren1 expression is significantly reduced following PKA inhibition with a corresponding loss in H3K27Ac and P300 binding at the locus. A restricted set of 9 genes with overlapping dynamically accessible regions, differential gene expression, and H3K27Ac and P300 binding were identified with roles among three primary renin regulatory paradigms. Conclusions: The data suggests that cAMP pathway inhibition controls renin expression through a reduction not in accessibility alone, but via a switch from an active to poised state of epigenetic control, a shift towards a less differentiated cellular identity, and the disruption of not only cAMP, but baroreceptor and Notch mediated renin regulatory pathways.

show abstract

Section: Atac-seq Reveals Distinct Clusters Of Dynamically Accessible...mentioning

confidence: 87%

Protein Kinase A Inhibition Epigenetically SilencesRen1

Smith,

Paxton,

Medrano

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…In addition, there are several previous evidences showing that dapagliflozin plays a protective role in the kidney and heart through lysosomal, phagocytic and autophagy pathways [ 47 – 49 ]. The protective effect of empagliflozin in non-diabetic chronic kidney disease (CKD) mice is partially mediated by the complement system, as demonstrated by RNA sequencing [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Effect of dapagliflozin on proteomics and metabolomics of serum from patients with type 2 diabetes

Liu,

Chang,

Ding

et al. 2023

Diabetol Metab Syndr

View full text Add to dashboard Cite

Background Sodium-glucose co-transporter 2 (SGLT2) inhibitors reduced the risk of cardiovascular and renal outcomes in patients with type 2 diabetes (T2D), but the underlying mechanism has not been well elucidated. The circulating levels of proteins and metabolites reflect the overall state of the human body. This study aimed to evaluate the effect of dapagliflozin on the proteome and metabolome in patients with newly diagnosed T2D. Methods A total of 57 newly diagnosed T2D patients were enrolled, and received 12 weeks of dapagliflozin treatment (10 mg/d, AstraZeneca). Serum proteome and metabolome were investigated at the baseline and after dapagliflozin treatment. Results Dapagliflozin significantly decreased HbA1c, BMI, and HOMA-IR in T2D patients (all p < 0.01). Multivariate models indicated clear separations of proteomics and metabolomics data between the baseline and after dapagliflozin treatment. A total of 38 differentially abundant proteins including 23 increased and 15 decreased proteins, and 35 differentially abundant metabolites including 17 increased and 18 decreased metabolites, were identified. In addition to influencing glucose metabolism (glycolysis/gluconeogenesis and pentose phosphate pathway), dapagliflozin significantly increased sex hormone-binding globulin, transferrin receptor protein 1, disintegrin, and metalloprotease-like decysin-1 and apolipoprotein A-IV levels, and decreased complement C3, fibronectin, afamin, attractin, xanthine, and uric acid levels. Conclusions The circulating proteome and metabolome in newly diagnosed T2D patients were significantly changed after dapagliflozin treatment. These changes in proteins and metabolites might be associated with the beneficial effect of dapagliflozin on cardiovascular and renal outcomes.

show abstract

“…In spontaneously hypertensive rats, dapagliflozin (10 mg/kg/day) for eight weeks reduced urinary albumin creatinine ratio but had no significant effect on serum creatinine levels or renal histological changes. However, transcriptome analysis showed that dapagliflozin therapy exerted protective effects on the renal tissues that were attributed to the alleviation of abnormal metabolism and inflammation [33]. Xuan et al [7] showed that dapagliflozin (10 mg/kg/day) treatment for seven days reduced renal fibrosis in a unilateral ureteral obstruction rat model.…”

Section: Sglt2i and Non-diabetic Kidney Dysfunction-preclinical Exper...mentioning

confidence: 99%

Sodium-Glucose Co-Transporter 2 Inhibitors: Mechanism of Action and Efficacy in Non-Diabetic Kidney Disease from Bench to Bed-Side

Abdelrahman,

Awad,

Abdel-Rahman

2024

JCM

View full text Add to dashboard Cite

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are currently available for the management of type 2 diabetes mellitus. SGLT2i acts by inhibiting renal SGLT2, thereby increasing glucosuria and lowering serum glucose. Recent trials are emerging supporting a role for SGLT2i irrespective of the diabetic status pointing towards that SGLT2i have other mechanisms of actions beyond blood sugar control. In this review, we will shed light on the role of this group of medications that act as SGLT2i in non-diabetics focusing on pre-clinical and clinical data highlighting the mechanism of renoprotection and effects of SGLT2i in the non-diabetic kidneys.

show abstract

RNA-Seq transcriptome analysis of renal tissue from spontaneously hypertensive rats revealed renal protective effects of dapagliflozin, an inhibitor of sodium-glucose cotransporter 2

Cited by 5 publications

References 68 publications

Protein Kinase A Inhibition Epigenetically SilencesRen1

Protein Kinase A Inhibition Epigenetically SilencesRen1

Effect of dapagliflozin on proteomics and metabolomics of serum from patients with type 2 diabetes

Sodium-Glucose Co-Transporter 2 Inhibitors: Mechanism of Action and Efficacy in Non-Diabetic Kidney Disease from Bench to Bed-Side

Contact Info

Product

Resources

About