Dapagliflozin attenuates early markers of diabetic nephropathy in fructose-streptozotocin-induced diabetes in rats

Oraby, Mamdouh A; El-Yamany, Mohammed F.; Safar, Marwa M.; Assaf, Naglaa; Ghoneim, Hamdy A.

doi:10.1016/j.biopha.2018.10.100

Cited by 55 publications

(32 citation statements)

References 62 publications

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“…Here, we proved that DAPA treatment minimizes the progression of renal functional and structural damage in STZinduced DKD. Beside improvement in classic renal retention parameters, DAPA also reduced both urinary and renal KIM-1 and NGAL by 50%, similar to what was recently observed in a T2DM model (39). Increased urinary and renal levels of KIM-1 and NGAL are not only highly sensitive indicators of tubular damage (3,36) but are also responsible for the development of renal inflammation and fibrosis (7,26).…”

Section: Dapa Diminishes Elevated Protein O-glcnacylation In the Kidnsupporting

confidence: 82%

Reduced O-GlcNAcylation and tubular hypoxia contribute to the antifibrotic effect of SGLT2 inhibitor dapagliflozin in the diabetic kidney

Hodrea

Balogh

Hosszú

et al. 2020

American Journal of Physiology-Renal Physiology

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Diabetic kidney disease is a worldwide epidemic, and therapies are incomplete. Clinical data suggest that improved renal outcomes by Na+-glucose cotransporter 2 inhibitor (SGLT2i) are partly beyond their antihyperglycemic effects; however, the mechanisms are still elusive. Here, we investigated the effect of the SGLT2i dapagliflozin (DAPA) in the prevention of elevated O-GlcNAcylation and tubular hypoxia as contributors of renal fibrosis. Type 1 diabetes was induced by streptozotocin in adult male Wistar rats. After the onset of diabetes, rats were treated for 6 wk with DAPA or DAPA combined with losartan (LOS). The effect of hyperglycemia was tested in HK-2 cells kept under normal or high glucose conditions. To test the effect of hypoxia, cells were kept in 1% O2 for 2 h. Cells were treated with DAPA or DAPA combined with LOS. DAPA slowed the loss of renal function, mitigated renal tubular injury markers (kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin), and reduced tubulointerstitial fibrosis. DAPA diminished high glucose-induced protein O-GlcNAcylation and moderated the tubular response to hypoxia through the hypoxia-inducible factor pathway. DAPA alone was as effective as combined treatment with LOS in all outcome parameters. These data highlight the role of ameliorated O-GlcNAcylation and diminished tubular hypoxia as important benefits of SGLT2i treatment. Our results support the link between glucose toxicity, tubular hypoxia, and fibrosis, a vicious trio that could be targeted by SGLT2i in kidney diseases of other origins as well.

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Section: Dapa Diminishes Elevated Protein O-glcnacylation In the Kidnsupporting

confidence: 82%

Reduced O-GlcNAcylation and tubular hypoxia contribute to the antifibrotic effect of SGLT2 inhibitor dapagliflozin in the diabetic kidney

Hodrea

Balogh

Hosszú

et al. 2020

American Journal of Physiology-Renal Physiology

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“…In this context, it has been shown that SGLT2i directly target podocytes and are effective by preserving the actin cytoskeleton structure 8 . In this respect, SGLT2i were reported to ameliorate glomerular and tubular injuries induced with streptozotocin and fructose in a rat DKD model 47 . In our study, we found that excretion of podx + and synpo + cells was significantly decreased at 6 months of follow‐up in the patients who received SGLT2i.…”

Section: Discussionsupporting

confidence: 51%

Effects of SGLT2 inhibitors on patients with diabetic kidney disease: A preliminary study on the basis of podocyturia

Durcan

Özkan

Saygı

et al. 2022

Journal of Diabetes

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Background: The aim of this study was to investigate the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on the glomerulus through the evaluation of podocyturia in patients with diabetic kidney disease (DKD). Methods:The study population was composed of 40 male patients with type 2 diabetes mellitus; 22 of them received SGLT2i (SGLT2i group), and the others who did not were the control. The DKD-related parameters of patients were monitored before SGLT2i initiation, and then in the third and sixth month of the follow-up period. Patients' demographic, clinical, laboratory, and follow-up data were obtained from medical charts. Microalbuminuria was measured in 24-h urine. The number of podocytes in the urine was determined by immunocytochemical staining of two different markers, namely podocalyxin (podx) and synaptopodin (synpo). Concentrations of urine stromal cell-derived factor 1a and vascular endothelial growth factor cytokines were quantified with an enzyme-linked immunosorbent assay kit. Results: At the end of the follow-up period, decreases in glycosylated hemoglobin, glucose, systolic and diastolic blood pressure, uric acid level, and microalbuminuria, and improvement in body mass index level and weight loss were significant for the SGLT2i group. On the other hand, there was no significant difference in terms of these parameters in the control group. The excretion of synaptopodin-positive (synpo + ) and podocalyxin-positive (podx + ) cells was significantly reduced at the end of the follow-up period for the SGLT2i group, while there was no significant change for the control.Conclusions: At the end of the follow-up period, male patients receiving SGLT2i had better DKD-related parameters and podocyturia levels compared to baseline and the control group. Our data support the notion that SGLT2i might have structural benefits for glomerular health.Emre Durcan and Serbay Ozkan have equally contributed to this manuscript.

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“…The vanin-1 expression, which increased after ROS accumulation, has served as the biomarker for oxidative stress within the kidney [ 99 ]. From the study by Oraby et al, SGLT2i alleviated the generation of vanin-1 [ 102 ]. SGLT2i also lessened the epithelial-to-mesenchymal transition by modulating miR21 [ 103 ].…”

Section: Metabolic Factors Influenced By Sglt2imentioning

confidence: 99%

Molecular Mechanisms of SGLT2 Inhibitor on Cardiorenal Protection

Hou

Zheng

Yen

et al. 2020

IJMS

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The development of sodium-glucose transporter 2 inhibitor (SGLT2i) broadens the therapeutic strategies in treating diabetes mellitus. By inhibiting sodium and glucose reabsorption from the proximal tubules, the improvement in insulin resistance and natriuresis improved the cardiovascular mortality in diabetes mellitus (DM) patients. It has been known that SGLT2i also provided renoprotection by lowering the intraglomerular hypertension by modulating the pre- and post- glomerular vascular tone. The application of SGLT2i also provided metabolic and hemodynamic benefits in molecular aspects. The recent DAPA-CKD trial and EMPEROR-Reduced trial provided clinical evidence of renal and cardiac protection, even in non-DM patients. Therefore, the aim of the review is to clarify the hemodynamic and metabolic modulation of SGLT2i from the molecular mechanism.

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Dapagliflozin attenuates early markers of diabetic nephropathy in fructose-streptozotocin-induced diabetes in rats

Cited by 55 publications

References 62 publications

Reduced O-GlcNAcylation and tubular hypoxia contribute to the antifibrotic effect of SGLT2 inhibitor dapagliflozin in the diabetic kidney

Reduced O-GlcNAcylation and tubular hypoxia contribute to the antifibrotic effect of SGLT2 inhibitor dapagliflozin in the diabetic kidney

Effects of SGLT2 inhibitors on patients with diabetic kidney disease: A preliminary study on the basis of podocyturia

Molecular Mechanisms of SGLT2 Inhibitor on Cardiorenal Protection

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