Dapagliflozin Ameliorates Diabetic Kidney Disease via Upregulating Crry and Alleviating Complement Over-activation in db/db Mice

Chang, Dong‐Yuan; Li, Xiaoqian; Chen, Min; Zhao, Ming‐Hui

doi:10.3389/fphar.2021.729334

Cited by 20 publications

(11 citation statements)

References 45 publications

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“…Complement C3 was proved to be negatively related to the glomerular filtration rate in patients with DN and could be immune-related biomarkers of DN ( 53 ). It has been reported that dapagliflozin can attenuate complement over-activation and upregulate the anti-inflammatory cytokine IL-10 in diabetic mice ( 30 , 54 ), which consisted with our results again. Recent studies showed that CASP3 was upregulated in diabetic rats and diabetic human kidney tubuli ( 55 , 56 ).…”

Section: Discussionsupporting

confidence: 92%

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An integrated RNA sequencing and network pharmacology approach reveals the molecular mechanism of dapagliflozin in the treatment of diabetic nephropathy

et al. 2022

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Dapagliflozin, an inhibitor of sodium-glucose cotransporter 2 (SGLT2), is a new type of oral hypoglycemic drugs which can promote glucose excretion in the kidney. Studies have shown that dapagliflozin has renoprotective effect in the treatment of type 2 diabetes. However, the underlying mechanism remains unclear. Here, we combined integrated RNA sequencing and network pharmacology approach to investigate the molecular mechanism of dapagliflozin for diabetic nephropathy (DN). Dapagliflozin significantly relieved glucose intolerance, urinary albumin/creatinine ratio (UACR) and renal pathological injuries of db/db mice. The LncRNA and mRNA expression in kidney tissues from control group (CR), db/db group (DN) and dapagliflozin group (DG) were assessed by RNA sequencing. We identified 7 LncRNAs and 64 mRNAs common differentially expressed in CR vs DN and DN vs DG, which were used to construct co-expression network to reveal significantly correlated expression patterns in DN. In addition, network pharmacology was used to predict the therapeutic targets of dapagliflozin and we constructed component-target-pathway network according to the results of RNA sequencing and network pharmacology. We found that SMAD9, PPARG, CD36, CYP4A12A, CYP4A12B, CASP3, H2-DMB2, MAPK1, MAPK3, C3 and IL-10 might be the pivotal targets of dapagliflozin for treating DN and these genes were mainly enriched in pathways including TGF-β signaling pathway, PPAR signaling pathway, Chemokine signaling pathway, etc. Our results have important implication and provide novel insights into the protective mechanism of dapagliflozin for treating DN.

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Section: Discussionsupporting

confidence: 92%

“…A recent study showed that dapagliflozin can enhanced fatty acid metabolism in DN mice ( 29 ). Dapagliflozin was demonstrated to ameliorate DN by promoting Crry and inhibiting complement over-activation in diabetic model ( 30 ). These reports supported our results.…”

Section: Discussionmentioning

confidence: 99%

An integrated RNA sequencing and network pharmacology approach reveals the molecular mechanism of dapagliflozin in the treatment of diabetic nephropathy

et al. 2022

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“…In contrast, SGLT2 inhibitors decrease the expression of HIF-1α, which may underlie the cardiorenal benefits of these drugs [34][35][36][37][38]. In addition, they upregulate sirtuin-1 [17,18], which directly and selectively activates HIF-2α by virtue of its effect to deacetylate specific lysine residues [39]; SGLT2 inhibitors have been shown to upregulate HIF-2α in the heart, potentially contributing to their antifibrotic actions [40].…”

Section: Distinctions In the Mechanism Of Erythropoietic Action Betwe...mentioning

confidence: 99%

Mechanistic and Clinical Comparison of the Erythropoietic Effects of SGLT2 Inhibitors and Prolyl Hydroxylase Inhibitors in Patients with Chronic Kidney Disease and Renal Anemia

Packer¹

2023

Am J Nephrol

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Renal anemia is treated with erythropoiesis-stimulating agents (ESAs), even though epoetin alfa and darbepoetin increase the risk of cardiovascular death and thromboembolic events, including stroke. Hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) inhibitors have been developed as an alternative to ESAs, producing comparable increases in hemoglobin. However, in advanced chronic kidney disease, HIF-PHD inhibitors can increase the risk of cardiovascular death, heart failure, and thrombotic events to a greater extent than that with ESAs, indicating that there is a compelling need for safer alternatives. Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of major cardiovascular events, and they increase hemoglobin, an effect that is related to an increase in erythropoietin and an expansion in red blood cell mass. SGLT2 inhibitors increase hemoglobin by ≈0.6–0.7 g/dL, resulting in the alleviation of anemia in many patients. The magnitude of this effect is comparable to that seen with low-to-medium doses of HIF-PHD inhibitors, and it is apparent even in advanced chronic kidney disease. Interestingly, HIF-PHD inhibitors act by interfering with the prolyl hydroxylases that degrade both HIF-1α and HIF-2α, thus enhancing both isoforms. However, HIF-2α is the physiological stimulus to the production of erythropoietin, and upregulation of HIF-1α may be an unnecessary ancillary property of HIF-PHD inhibitors, which may have adverse cardiac and vascular consequences. In contrast, SGLT2 inhibitors act to selectively increase HIF-2α, while downregulating HIF-1α, a distinctive profile that may contribute to their cardiorenal benefits. Intriguingly, for both HIF-PHD and SGLT2 inhibitors, the liver is likely to be an important site of increased erythropoietin production, recapitulating the fetal phenotype. These observations suggest that the use of SGLT2 inhibitors should be seriously evaluated as a therapeutic approach to treat renal anemia, yielding less cardiovascular risk than other therapeutic options.

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“…Noteworthily, the administration time of 6 days - 8 weeks is not enough for studying the role of DAPA in DKD associated with its regulation of the gut microbiota. As DAPA is generally continuously used in the long-period treatment of DKD in clinical practice and SGLT2 inhibitors, especially DAPA, are often administrated for 10-12w or longer time rather than 6 days – 8 weeks or less time for the treatment of DKD in db/db mice ( 21 , 28 – 30 ); future studies should explore whether DAPA as a novel therapy for DKD can regulate the gut flora and we assumed that the prolonged intervention of DAPA has further benefits. To our knowledge, we firstly suggest that the protective effect of DAPA on DKD may be related to the improvement of the gut microbiota and investigate the impacts of DAPA on the gut flora in the DKD mice over time.…”

Section: Introductionmentioning

confidence: 99%

Sodium glucose co-transporter 2 (SGLT2) inhibition via dapagliflozin improves diabetic kidney disease (DKD) over time associatied with increasing effect on the gut microbiota in db/db mice

Chen²,

Yang³

et al. 2023

Front. Endocrinol.

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BackgroundThe intestinal microbiota disorder gradually aggravates during the progression of diabetes. Dapagliflozin (DAPA) can improve diabetes and diabetic kidney disease(DKD). However, whether the gut microbiota plays a role in the protection of DAPA for DKD remains unclear.MethodsTo investigate the effects of DAPA on DKD and gut microbiota composition during disease progression, in our study, we performed 16S rRNA gene sequencing on fecal samples from db/m mice (control group), db/db mice (DKD model group), and those treated with DAPA (treat group) at three timepoints of 14weeks\18weeks\22weeks.ResultsWe found that DAPA remarkably prevented weight loss and lowered fasting blood glucose in db/db mice during disease progression, eventually delaying the progression of DKD. Intriguingly, the study strongly suggested that there is gradually aggravated dysbacteriosis and increased bile acid during the development of DKD. More importantly, comparisons of relative abundance at the phylum level and partial least squares-discriminant analysis (PLS-DA) plots roughly reflected that the effect of DAPA on modulating the flora of db/db mice increased with time. Specifically, the relative abundance of the dominant Firmicutes and Bacteroidetes was not meaningfully changed among groups at 14 weeks as previous studies described. Interestingly, they were gradually altered in the treat group compared to the model group with a more protracted intervention of 18 weeks and 22 weeks. Furthermore, the decrease of Lactobacillus and the increase of norank_f:Muribaculaceae could account for the differences at the phylum level observed between the treat group and the model group at 18 weeks and 22 weeks.ConclusionWe firstly found that the protective effect of DAPA on DKD may be related to the dynamic improvement of the gut microbiota over time, possibly associated with the impact of DAPA on the bile acid pool and its antioxidation effect.

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Dapagliflozin Ameliorates Diabetic Kidney Disease via Upregulating Crry and Alleviating Complement Over-activation in db/db Mice

Cited by 20 publications

References 45 publications

An integrated RNA sequencing and network pharmacology approach reveals the molecular mechanism of dapagliflozin in the treatment of diabetic nephropathy

An integrated RNA sequencing and network pharmacology approach reveals the molecular mechanism of dapagliflozin in the treatment of diabetic nephropathy

Mechanistic and Clinical Comparison of the Erythropoietic Effects of SGLT2 Inhibitors and Prolyl Hydroxylase Inhibitors in Patients with Chronic Kidney Disease and Renal Anemia

Sodium glucose co-transporter 2 (SGLT2) inhibition via dapagliflozin improves diabetic kidney disease (DKD) over time associatied with increasing effect on the gut microbiota in db/db mice

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