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Empagliflozin attenuates acute kidney injury after myocardial infarction in diabetic rats.

ABSTRACT: Acute kidney injury (AKI) predicts poor prognosis in patients with acute myocardial infarction (MI) and diabetes mellitus (DM) is an independent risk factor of AKI. Recent clinical studies have shown the beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on cardiovascular and renal outcomes in patients with DM. We recently reported that canagliflozin normalized susceptibility of diabetic rats to AKI after acute MI via ?-hydroxybutyrate-mediated suppression of NOX expression. Here we examined whether the same renoprotective effect is shared by empagliflozin. Serum creatinine levels were not changed by MI induced by coronary artery occlusion in LETO, non-diabetic control rats, and OLETF, obese type 2 diabetic rats. However, immunohistochemistry revealed that MI increased renal expression of NGAL and KIM-1, early markers of tubular injury, by 3.2-fold and 2.6-fold, respectively, in OLETF. These increases in injury markers were not observed in LETO. Pretreatment with empagliflozin of OLETF for 2 weeks improved hyperglycemia, increased blood ?-hydroxybutyrate level, and suppressed MI-induced expression of NGAL and KIM-1. Empagliflozin suppressed upregulation of NOX2 and NOX4 in the kidney of OLETF. Taken together with the results of our previous study, it was concluded that treatment with the SGLT2 inhibitor protects the diabetic kidney from MI-induced AKI.

SUBMITTER: Kuno A

PROVIDER: S-EPMC7190820 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Empagliflozin attenuates acute kidney injury after myocardial infarction in diabetic rats.

Kuno Atsushi A Kimura Yukishige Y Mizuno Masashi M Oshima Hiroto H Sato Tatsuya T Moniwa Norihito N Tanaka Marenao M Yano Toshiyuki T Tanno Masaya M Miki Takayuki T Miura Tetsuji T

Scientific reports 20200429 1

Acute kidney injury (AKI) predicts poor prognosis in patients with acute myocardial infarction (MI) and diabetes mellitus (DM) is an independent risk factor of AKI. Recent clinical studies have shown the beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on cardiovascular and renal outcomes in patients with DM. We recently reported that canagliflozin normalized susceptibility of diabetic rats to AKI after acute MI via β-hydroxybutyrate-mediated suppression of NOX expression. ...[more]

PMID: 32350374

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Project description:AimsSodium-glucose co-transporter 2 inhibition reduces the risk of hospitalization for heart failure and for death in patients with symptomatic heart failure. However, trials investigating the effects of this drug class in patients following acute myocardial infarction are lacking.Methods and resultsIn this academic, multicentre, double-blind trial, patients (n = 476) with acute myocardial infarction accompanied by a large creatine kinase elevation (>800 IU/L) were randomly assigned to empagliflozin 10 mg or matching placebo once daily within 72 h of percutaneous coronary intervention. The primary outcome was the N-terminal pro-hormone of brain natriuretic peptide (NT-proBNP) change over 26 weeks. Secondary outcomes included changes in echocardiographic parameters. Baseline median (interquartile range) NT-proBNP was 1294 (757-2246) pg/mL. NT-proBNP reduction was significantly greater in the empagliflozin group, compared with placebo, being 15% lower [95% confidence interval (CI) -4.4% to -23.6%] after adjusting for baseline NT-proBNP, sex, and diabetes status (P = 0.026). Absolute left-ventricular ejection fraction improvement was significantly greater (1.5%, 95% CI 0.2-2.9%, P = 0.029), mean E/e' reduction was 6.8% (95% CI 1.3-11.3%, P = 0.015) greater, and left-ventricular end-systolic and end-diastolic volumes were lower by 7.5 mL (95% CI 3.4-11.5 mL, P = 0.0003) and 9.7 mL (95% CI 3.7-15.7 mL, P = 0.0015), respectively, in the empagliflozin group, compared with placebo. Seven patients were hospitalized for heart failure (three in the empagliflozin group). Other predefined serious adverse events were rare and did not differ significantly between groups.ConclusionIn patients with a recent myocardial infarction, empagliflozin was associated with a significantly greater NT-proBNP reduction over 26 weeks, accompanied by a significant improvement in echocardiographic functional and structural parameters.Clinicaltrials.gov registrationNCT03087773.

Project description:BackgroundData on the association between obesity and acute kidney injury (AKI) in patients with ST-elevation myocardial infarction (STEMI) are sparse and inconclusive. We aimed to evaluate the association between obesity and AKI and the outcome in these patients.MethodsA retrospective observational study of 3979 STEMI patients undergoing percutaneous coronary intervention (PCI) was performed at a single center. Patients with and without AKI were compared. Patients were also divided into three categories according to BMI, and these were compared. All-cause mortality was determined at 30 days and over a median period of 7.0 years.ResultsThe incidence of AKI was similar in all BMI categories. There was no association between BMI categories and AKI (p = 0.089). The Spearman correlation coefficient between BMI categories and AKI showed no correlation (r = -0.005; p = 0.75). More AKI patients died within 30 days and in the long term [137 (18.5%) and 283 (38.1%) patients in the AKI group died compared to 118 (3.6%) and 767 (23.1%) in the non-AKI group; p < 0.0001]. AKI was harmful in all BMI categories (p < 0.0001) and was associated with more than a 2.5-fold and a 1.5-fold multivariable-adjusted 30-day and long-term mortality risk, respectively (aOR 2.59; 95% CI 1.84-3.64; p < 0.0001, aHR 1.54; 95% CI 1.32-1.80; p < 0.0001). BMI categories were not associated with 30-day mortality (p = 0.26) but were associated with long-term mortality (p < 0.0001). Overweight and obese patients had an approximately 25% lower long-term multivariable-adjusted risk of death than normal-weight patients. In patients with AKI, BMI was only associated with long-term risk (p = 0.022). Obesity had an additional beneficial effect in these patients, and only patients with obesity, but not overweight patients, had a lower multivariable adjusted long-term mortality risk than normal-weight patients (aHR 062; 95% CI 0.446-0.88 p = 0.007).ConclusionsIn patients who experienced AKI, obesity had an additional positive modifying effect. Our data suggest that the incidence of AKI in STEMI patients is not BMI-dependent.

Project description:Diabetic nephropathy (DN) is the primary cause of end?stage renal disease, which is closely associated with dysfunction of the podocytes, the main component of the glomerular filtration membrane; however, the exact underlying mechanism is unknown. Polyamines, including spermine, spermidine and putrescine, have antioxidant and anti?aging properties that are involved in the progression of numerous diseases, but their role in DN has not yet been reported. The present study aimed to explore the role of polyamines in DN, particularly in podocyte injury, and to reveal the molecular mechanism underlying the protective effect of exogenous spermine. Streptozotocin intraperitoneal injection?induced type 1 diabetic (T1D) rat models and high glucose (HG)?stimulated podocyte injury models were established. It was found that in T1D rat kidneys and HG?induced podocytes, ornithine decarboxylase (a key enzyme for polyamine synthesis) was downregulated, while spermidine/spermine N1?acetyltransferase (a key enzyme for polyamines degradation) was upregulated, which suggested that reduction of the polyamine metabolic pool particularly decreased spermine content, is a major factor in DN progression. In addition, hyperglycemia can induce an increased rat kidney weight ratio, serum creatinine, urea, urinary albumin excretion and glomerular cell matrix levels, and promote mesangial thickening and loss or fusion of podocytes. The expression levels of podocyte marker proteins (nephrin, CD2?associated protein and podocin) and autophagy?related proteins [autophagy protein 5, microtube?associated proteins 1A/1B light chain 3 (LC3)II/LC3I, Beclin 1 and phosphorylated (p)?AMPK] were downregulated, while cleaved caspase?3, P62 and p?mTOR were increased. These changes could be improved by pretreatment with exogenous spermine or rapamycin (autophagic agonist). In conclusion, spermine may have the potential to prevent diabetic kidney injury in rats by promoting autophagy via regulating the AMPK/mTOR signaling pathway.

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Empagliflozin attenuates acute kidney injury after myocardial infarction in diabetic rats.

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Empagliflozin attenuates acute kidney injury after myocardial infarction in diabetic rats.

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