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Kidney Week

Abstract: PO0447

SGLT-2 Inhibitor Dapagliflozin Does Not Improve Severe Ischemia-Reperfusion-Induced AKI

Session Information

  • AKI: Novel Insights
    November 04, 2021 | Location: On-Demand, Virtual Only
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Tumova, Jana, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
  • Kim, Jiwan John, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
  • Venkatachalam, Manjeri A., The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
  • Sharma, Kumar, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States
Background

Acute kidney injury (AKI) is defined by a rapid decline in the kidney function, occurs in approximately 5-20% hospitalized patients and is associated with high mortality. Renal ischemia-reperfusion (IR) injury is a leading cause of AKI. Despite intensive research and progress in understanding the pathophysiological mechanisms, IR-AKI remains a critical problem without any effective treatment available. Dapagliflozin is a novel antidiabetic drug from the class of sodium-glucose cotransporter 2 (SGLT2) inhibitors that reduce glucose reabsorption in renal proximal tubules. SGLT2 inhibitors have been recently suggested to cause protection even in renal injury conditions beyond diabetes, such as AKI. In our work, we aimed to test the effectivity of dapagliflozin in decreasing kidney injury in a mouse model of severe IR-AKI.

Methods

We developed a mouse model of severe IR-AKI. C57BL/6J males underwent 35 minutes of renal ischemia by bilateral clamping of renal pedicles followed by 24h of reperfusion. The levels of blood urea nitrogen (BUN) and plasma creatinine at 24h after reperfusion were high but all mice undergoing IR surgery survived. Histological analysis showed severe tubular injury in the outer stripe of outer medulla. Mice undergoing IR surgery were divided into groups and received either no treatment, 1 mg/kg dapagliflozin, 10 mg/kg dapagliflozin or vehicle only administered by oral gavage 24h and 1h before the onset of ischemia. BUN and other parameters of kidney function were assessed 24h after reperfusion.

Results

In our preliminary data oral administration of dapagliflozin did not prevent kidney function decline in the model of severe IR-AKI. The BUN levels in plasma at 24h after reperfusion were not significantly different in groups of mice undergoing IR surgery. This is in contrast to previously published study1 where, however, less severe model of IR-AKI with 27 minutes of renal ischemia was used.

Conclusion

Dapagliflozin did not improve severe IR-AKI. We hypothesize that dapagliflozin may be effective in improving less severe kidney injury, however, lacks effectivity in more severe cases of AKI. In our future studies, we would like to test the ability of dapagliflozin to prevent kidney injury at different stages of IR-AKI.

1Chang et al. PLoS One. 2016;11(7):e0158810.

Funding

  • Other U.S. Government Support