SGLT2 inhibitor empagliflozin monotherapy alleviates renal oxidative stress in albino Wistar diabetic rats after myocardial infarction induction

Ahmed, Ahmed; Mona, Mohamed H.; Abdel-Kareem, Mona A.; Elsisy, Rasha A.

doi:10.1016/j.biopha.2021.111624

Cited by 8 publications

(4 citation statements)

References 42 publications

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“…Our data on the nephroprotective effects of SGLT2 inhibition by empagliflozin fits to previous findings in patients with diabetes ( 8 – 10 ) and also to findings in animal models of diabetic nephropathy ( 36 – 38 ) and even to findings in nondiabetic nephropathy models ( 39 – 43 ), However, there are also some studies showing no effect of SGLT2 inhibition in nondiabetic CKD models. Nishiyama et al ( 44 ) found that SGLT2 inhibitor (TA-1887, 10 mg/kg/day) treatment of 5/6 nephrectomized rats for 10 wk had no beneficial effects on serum creatinine clearance, proteinuria and renal tissue structure.…”

Section: Discussionsupporting

confidence: 91%

Renoprotective effects of empagliflozin are linked to activation of the tubuloglomerular feedback mechanism and blunting of the complement system

Chen

Delić

Cao

et al. 2023

American Journal of Physiology-Cell Physiology

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The mechanisms of nephroprotection in non-diabetic chronic kidney disease (CKD) models by sodium-glucose cotransporter 2 (SGLT2) inhibitors are not well defined. Five groups were established: sham operated rats, placebo treated rats with 5/6 nephrectomy (5/6Nx); 5/6Nx + telmisartan (5mg/kg/day), 5/6Nx + empagliflozin (3mg/kg/day); 5/6Nx + empagliflozin (15mg/kg/day). Treatment duration was 95 days. Empagliflozin showed a dose-dependent beneficial effect on the change from baseline of estimated glomerular filtration rate (eGFR). The urinary albumin to creatinine ratio likewise improved in a dose-dependent manner. Both dosages of empagliflozin improved morphological kidney damage parameters such as renal interstitial fibrosis and glomerulosclerosis. 5/6 nephrectomy led to a substantial reduction of urinary adenosine excretion, a surrogate parameter of the tubuloglomerular feedback mechanism (TGF). Empagliflozin caused a dose-dependent increase in urinary adenosine excretion. The urinary adenosine excretion was negatively correlated with interstitial kidney fibrosis and positively correlated with eGFR. Immunohistochemical analysis revealed that empagliflozin had no effect on CD8+ and CD4+ T-cells as well as on CD68+ cells (macrophages). To further explore potential mechanisms, a non-hypothesis driven approach was used. RNA sequencing followed by quantitative real-time polymerase chain reaction revealed that complement component 1Q subcomponent A chain (C1qa) as well as complement component 1Q subcomponent C chain (C1qc) gene expression were upregulated in the placebo-treated 5/6Nx rats and this upregulation was blunted by treatment with empagliflozin. In conclusion, empagliflozin mediated-nephroprotection in non-diabetic CKD is due to a dose dependent activation of the TGF as well as empagliflozin mediated effects on the complement system.

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Section: Discussionsupporting

confidence: 91%

Renoprotective effects of empagliflozin are linked to activation of the tubuloglomerular feedback mechanism and blunting of the complement system

Chen

Delić

Cao

et al. 2023

American Journal of Physiology-Cell Physiology

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“… 31 Basic research in a rat model has also shown that SGLT2i attenuates AKI after myocardial infarction by alleviating oxidative stress. 26 To our knowledge, the associations between SGLT2i and a lower risk of AKI with shock and respiratory failure have not yet been reported. Further studies are needed to confirm these findings.…”

Section: Discussionmentioning

confidence: 90%

“…22 SGLT2is could also protect kidney cells from hypoxic injury through cellular signaling and decrease inflammation. 24 Finally, mounting basic research evidence suggests that SGLT2i use benefits sepsis-, 25 heart failure-, 26 contrast media-, 27 and nephrotoxin-associated AKI. 28 AKI is a syndrome that rarely has a sole distinct pathophysiology cause.…”

Section: Discussionmentioning

confidence: 99%

“…A recent meta-analysis of acute heart failure trials also detected an association between reduced AKI risk and SGLT2i use . Basic research in a rat model has also shown that SGLT2i attenuates AKI after myocardial infarction by alleviating oxidative stress . To our knowledge, the associations between SGLT2i and a lower risk of AKI with shock and respiratory failure have not yet been reported.…”

Section: Discussionmentioning

confidence: 99%

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Sodium-Glucose Transport Protein 2 Inhibitor Use for Type 2 Diabetes and the Incidence of Acute Kidney Injury in Taiwan

et al. 2023

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ImportanceThe association between sodium-glucose transport protein 2 inhibitor (SGLT2i) use and the incidence of acute kidney injury (AKI) remains controversial. The benefits of SGLT2i use in patients to reduce AKI requiring dialysis (AKI-D) and concomitant diseases with AKI as well as improve AKI prognosis have not yet been established.ObjectiveTo investigate the association between SGLT2i use and AKI incidence in patients with type 2 diabetes (T2D).Design, Setting, and ParticipantsThis nationwide retrospective cohort study used the National Health Insurance Research Database in Taiwan. The study analyzed a propensity score–matched population of 104 462 patients with T2D treated with SGLT2is or dipeptidyl peptidase 4 inhibitors (DPP4is) between May 2016 and December 2018. All participants were followed up from the index date until the occurrence of outcomes of interest, death, or the end of the study, whichever was earliest. Analysis was conducted between October 15, 2021, and January 30, 2022.Main Outcomes and MeasuresThe primary outcome was the incidence of AKI and AKI-D during the study period. AKI was diagnosed using International Classification of Diseases diagnostic codes, and AKI-D was determined using the diagnostic codes and dialysis treatment during the same hospitalization. Conditional Cox proportional hazard models assessed the associations between SGLT2i use and the risks of AKI and AKI-D. The concomitant diseases with AKI and its 90-day prognosis, ie, the occurrence of advanced chronic kidney disease (CKD stage 4 and 5), end-stage kidney disease, or death, were considered when exploring the outcomes of SGLT2i use.ResultsIn a total of 104 462 patients, 46 065 (44.1%) were female patients, and the mean (SD) age was 58 (12) years. After a follow-up of approximately 2.50 years, 856 participants (0.8%) had AKI and 102 (&lt;0.1%) had AKI-D. SGLT2i users had a 0.66-fold risk for AKI (95% CI, 0.57-0.75; P &lt; .001) and 0.56-fold risk of AKI-D (95% CI, 0.37-0.84; P = .005) compared with DPP4i users. The numbers of patients with AKI with heart disease, sepsis, respiratory failure, and shock were 80 (22.73%), 83 (23.58%), 23 (6.53%), and 10 (2.84%), respectively. SGLT2i use was associated with lower risk of AKI with respiratory failure (hazard ratio [HR], 0.42; 95% CI, 0.26-0.69; P &lt; .001) and shock (HR, 0.48; 95% CI, 0.23-0.99; P = .048) but not AKI with heart disease (HR, 0.79; 95% CI, 0.58-1.07; P = .13) and sepsis (HR, 0.77; 95% CI, 0.58-1.03; P = .08). The 90-day AKI prognosis for the risk of advanced CKD indicated a 6.53% (23 of 352 patients) lower incidence in SGLT2i users than in DPP4i users (P = .045).Conclusions and RelevanceThe study findings suggest that patients with T2D who receive SGLT2i may have lower risk of AKI and AKI-D compared with those who receive DPP4i.

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Empagliflozin activates Wnt/β-catenin to stimulate FUNDC1-dependent mitochondrial quality surveillance against type-3 cardiorenal syndrome

Cai

Zhuang

et al. 2022

Molecular Metabolism

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SGLT2 inhibitor empagliflozin monotherapy alleviates renal oxidative stress in albino Wistar diabetic rats after myocardial infarction induction

Cited by 8 publications

References 42 publications

Renoprotective effects of empagliflozin are linked to activation of the tubuloglomerular feedback mechanism and blunting of the complement system

Renoprotective effects of empagliflozin are linked to activation of the tubuloglomerular feedback mechanism and blunting of the complement system

Sodium-Glucose Transport Protein 2 Inhibitor Use for Type 2 Diabetes and the Incidence of Acute Kidney Injury in Taiwan

Empagliflozin activates Wnt/β-catenin to stimulate FUNDC1-dependent mitochondrial quality surveillance against type-3 cardiorenal syndrome

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