Kidney Week

Abstract: SA-PO151

Dapagliflozin Attenuates Tubular Injury and Ferroptosis after AKI in Diabetic and Nondiabetic Mice

Session Information

• AKI: Metabolism and Cell Death
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Sato, Tetta, Chiba Daigaku Daigakuin Igaku Kenkyuin Igakubu, Chiba, Chiba, Japan

Tetta Sato, MD

• Ide, Shintaro, Chiba Daigaku Daigakuin Igaku Kenkyuin Igakubu, Chiba, Chiba, Japan

Shintaro Ide, MD, PhD

• Ide, Kana, Chiba Daigaku Daigakuin Igaku Kenkyuin Igakubu, Chiba, Chiba, Japan

Kana Ide, MD

• Yamaguchi, Ayano, Chiba Daigaku Daigakuin Igaku Kenkyuin Igakubu, Chiba, Chiba, Japan

Ayano Yamaguchi, MD

• Teramoto, Naoya, Chiba Daigaku Daigakuin Igaku Kenkyuin Igakubu, Chiba, Chiba, Japan

Naoya Teramoto, MD, PhD

• Maezawa, Yoshiro, Chiba Daigaku Daigakuin Igaku Kenkyuin Igakubu, Chiba, Chiba, Japan

Yoshiro Maezawa, MD, PhD

• Yokote, Koutaro, Chiba Daigaku, Chiba, Chiba, Japan

Koutaro Yokote, MD, PhD

Background

Diabetes Kidney disease (DKD) is the most common cause of chronic kidney disease (CKD) and end-stage renal disease. Diabetic patients are at a higher risk of acute kidney injury (AKI), which can lead to the rapid deterioration of kidney function, suggesting that AKI is a potential risk factor for DKD without albuminuria. Although several studies have shown sodium-glucose cotransporter 2 (SGLT2) inhibitors have a renoprotective effect in both diabetic and non-diabetic patients, it remains unclear whether SGLT2 inhibitors are protective in AKI and its transition to CKD, with or without diabetes.

Methods

To clarify the effect of an SGLT2 inhibitor in AKI and its mechanism, we performed unilateral ischemia-reperfusion injury (uIRI) in type 2 diabetic mice (db/db). We then divided these mice into two groups: one treated with Dapagliflozin (DAPA), an SGLT2 inhibitor, and the other treated with vehicle. We also performed uIRI on C57B6J (WT) mice and compared kidney phenotypes between the DAPA and vehicle groups to reveal this effect independently of glycemic control. We used histological analysis, immunofluorescence, and quantitative PCR to evaluate kidney injury.

Results

Db/db uIRI kidneys with vehicle showed severe tubular injury (ex. Vcam1, Havcr1), accumulation of inflammatory cells, and fibrosis. In contrast, treatment with DAPA significantly reduced tubular injury in db/db uIRI kidneys, indicating a protective effect of DAPA against AKI and AKI to CKD transition. This protective effect was also seen in WT uIRI kidneys. To understand the mechanism, we focused on ferroptosis, a non-apoptotic cell death process that plays a key role in diseases, such as DKD, AKI, and AKI to CKD transition. Db/db uIRI kidneys and WT uIRI kidneys with the vehicle showed increased ferroptosis, characterized by 4-Hydroxynonenal (4HNE) and TUNEL positivity. However, treatment with DAPA reduced these markers in both groups.

Conclusion

Our data demonstrate that Dapagliflozin attenuates kidney tubular injury and reduces ferroptosis, thereby mitigating AKI to CKD transition after AKI. The renoprotective effect of SGLT2 inhibitors appears to be mediated through suppressing ferroptosis. These findings would provide new insights into the potential treatment of AKI in patients with diabetes.

Funding

• Government Support – Non-U.S.