Acute Dapagliflozin Administration Ameliorates Cardiac Surgery-Associated Acute Kidney Injury in a Rabbit Model.

BACKGROUND: Several studies have shown that sodium-glucose cotransporter-2 inhibitors have a renoprotective effect on acute kidney injury (AKI), but their effect on cardiac surgery-associated AKI is unknown. METHODS AND RESULTS: AKI was induced in 25 rabbits without diabetes mellitus by cardiopulmonary bypass (CPB) for 2 h and they were divided into 5 groups: sham; dapagliflozin-treated sham; CPB; dapagliflozin-treated CPB; and furosemide-treated CPB (n=5 in each group). Dapagliflozin was administered via the femoral vein before initiating CPB. Kidney tissue and urine and blood samples were collected after the surgical procedure. There were no differences in the hemodynamic variables of each group. Dapagliflozin reduced serum creatinine and blood urea nitrogen concentrations, and increased overall urine output (all P<0.05). Hematoxylin and eosin staining showed that the tubular injury score was improved after dapagliflozin administration (P<0.01). Dapagliflozin administration mitigated reactive oxygen species and kidney injury molecule-1 as assessed by immunohistochemistry (both P<0.0001). Protein expression analysis showed improvement of inflammatory cytokines and apoptosis, and antioxidant enzyme expression was elevated (all P<0.05) through activation of the nuclear factor erythroid 2-related factor 2 pathway (P<0.01) by dapagliflozin. CONCLUSIONS: Acute intravenous administration of dapagliflozin protects against CPB-induced AKI. Dapagliflozin may have direct renoprotective effects in renal tubular cells.

Necrostatin-1 Attenuates Delayed Paraplegia after Transient Spinal Cord Ischemia in Rabbits by Inhibiting the Upregulation of Receptor-Interacting Protein Kinase 1 and 3.

BACKGROUND: Delayed-onset paraplegia is a disastrous complication after thoracoabdominal aortic open surgery and thoracic endovascular aortic repair. Studies have revealed that transient spinal cord ischemia caused by temporary occlusion of the aorta induces delayed motor neuron death owing to apoptosis and necroptosis. Recently, necrostatin-1 (Nec-1), a necroptosis inhibitor, has been reported to reduce cerebral and myocardial infarction in rats or pigs. In this study, we investigated the efficacy of Nec-1 in delayed paraplegia after transient spinal cord ischemia in rabbits and assessed the expression of necroptosis- and apoptosis-related proteins in motor neurons. METHODS: This study used rabbit transient spinal cord ischemia models using a balloon catheter. They were divided into a vehicle-treated group (n = 24), Nec-1-treated group (n = 24), and sham-controls (n = 6). In the Nec-1-treated group, 1 mg/kg of Nec-1 was intravascularly administered immediately before ischemia induction. Neurological function was assessed using the modified Tarlov score, and the spinal cord was removed 8 hr and 1, 2, and 7 days after reperfusion. Morphological changes were examined using hematoxylin and eosin staining. The expression levels of necroptosis-related proteins (receptor-interacting protein kinase [RIP] 1 and 3) and apoptosis-related proteins (Bax and caspase-8) were assessed using western blotting and histochemical analysis. We also performed double-fluorescence immunohistochemical studies of RIP1, RIP3, Bax, and caspase-8. RESULTS: Neurological function significantly improved in the Nec-1-treated group compared with that in the vehicle-treated group 7 days after reperfusion (median 3 and 0, P = 0.025). Motor neurons observed 7 days after reperfusion were significantly decreased in both groups compared with the sham group (vehicle-treated, P < 0.001; Nec-1-treated, P < 0.001). However, significantly more motor neurons survived in the Nec-1-treated group than in the vehicle-treated group (P < 0.001). Western blot analysis revealed RIP1, RIP3, Bax, and caspase-8 upregulation 8 hr after reperfusion in the vehicle-treated group (RIP1, P = 0.001; RIP3, P = 0.045; Bax, P = 0.042; caspase-8, P = 0.047). In the Nec-1-treated group, the upregulation of RIP1 and RIP3 was not observed at any time point, whereas that of Bax and caspase-8 was observed 8 hr after reperfusion (Bax, P = 0.029; caspase-8, P = 0.021). Immunohistochemical study revealed the immunoreactivity of these proteins in motor neurons. Double-fluorescence immunohistochemistry revealed the induction of RIP1 and RIP3, and that of Bax and caspase-8, in the same motor neurons. CONCLUSIONS: These data suggest that Nec-1 reduces delayed motor neuron death and attenuates delayed paraplegia after transient spinal cord ischemia in rabbits by selectively inhibiting necroptosis of motor neurons with minimal effect on their apoptosis.