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Kidney Week

Abstract: SA-PO188

Transient Inhibition of the Sodium-Glucose Cotransporter 2 After Ischemia/Reperfusion Injury Ameliorates CKD in Rats

Session Information

  • AKI: Mechanisms - III
    November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Martinez-Rojas, Miguel Angel, Universidad Nacional Autonoma de Mexico Instituto de Investigaciones Biomedicas, Ciudad de Mexico, Ciudad de México, Mexico
  • Balcázar, Hiram, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Ciudad de Mexico, Ciudad de México, Mexico
  • González Soria, Isaac, Universidad Nacional Autonoma de Mexico Facultad de Medicina, Ciudad de Mexico, Ciudad de México, Mexico
  • Gonzalez Rivera, Jesus Manuel, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Ciudad de Mexico, Ciudad de México, Mexico
  • Rodríguez Vergara, Mauricio Ernesto, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Ciudad de Mexico, Ciudad de México, Mexico
  • Velázquez Villegas, Laura Alejandra, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Ciudad de Mexico, Ciudad de México, Mexico
  • Pérez-Villalva, Rosalba, Universidad Nacional Autonoma de Mexico Instituto de Investigaciones Biomedicas, Ciudad de Mexico, Ciudad de México, Mexico
  • Bobadilla, Norma, Universidad Nacional Autonoma de Mexico Instituto de Investigaciones Biomedicas, Ciudad de Mexico, Ciudad de México, Mexico
Background

A severe episode of Acute Kidney Injury (AKI) can lead to Chronic Kidney Disease (CKD). The sodium-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin, has exhibited nephroprotective actions in CKD, but the specific mechanisms remain elusive. We evaluated if a transient administration of Dapa after ischemia/reperfusion injury (IRI) prevents CKD.

Methods

Forty-one male Wistar rats (300-350 g) were randomized in: Sham surgery, IRI for 30 min (IR), and IRI + dapagliflozin (IR+Dapa). Daily treatment with Dapa was initiated 24 h after IRI and maintained only 10 days. After this period, one half of rats was euthanized for kidney functional, histological, and molecular analyses. The other half was followed for 5 months. Proteinuria was determined monthly; kidney function and fibrosis were evaluated at the 5th month. Differences between groups were analyzed through ANOVA with a significance level of p<0.05.

Results

Ten days after IRI, rats receiving Dapa exhibited an early restoration of renal blood flow (RBF) with a notorious reduction in RVR and a recovered Creatinine Clearance (CrCl) compared to the IR group alone. Importantly, IR rats persisted with detrimental changes in mitochondrial homeostasis indicated by a significant decrease in Sirtuin-3, a low Mitofusin/Drp1 ratio, and an abnormal mitophagy process with PINK1 up-regulation and reduced Parkin. There was a reduction in OXPHOS Complex I and less total NAD/NADH levels in this group. Interestingly, all these changes were prevented with SGLT2 inhibition. We also demonstrated that this short treatment prevented CKD after five months as indicated by proteinuria, CrCl, and fibrosis.

Conclusion

A short treatment with dapagliflozin after IRI is enough to prevent maladaptive repair and CKD in rats. This renoprotective effect seems to be mediated by an improved renal circulation and restoration of mitochondrial homeostasis. These findings highlight the relevance of the initial days of reperfusion, indicating that maladaptive repair can be modulated after severe AKI to prevent the development of long-term consequences.

Funding

  • Government Support – Non-U.S.