Defective autophagy and AMPK inactivation drive ferroptosis in diabetic kidney disease

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Abstract
Aims/hypothesis Ferroptosis, a regulated form of cell death characterised by excessive lipid peroxidation, plays a critical role in acute kidney injury (AKI). Individuals with diabetes have an elevated risk of developing AKI. However, the contribution of ferroptosis to the heightened susceptibility to AKI in diabetic kidney disease (DKD) remains unclear. This study aimed to investigate whether DKD influences ferroptosis susceptibility in proximal tubular epithelial cells (PTECs), focusing on autophagy and AMP-activated protein kinase (AMPK) signalling. Methods We examined the association between ferroptotic signatures and autophagy/AMPK pathways in human kidney biopsy specimens. To explore the roles of autophagy and AMPK in modulating ferroptosis in PTECs during DKD, we subjected streptozocin (STZ)-induced type 1 diabetic mice and type 2 diabetic db/db mice to ischaemia–reperfusion injury. Primary Atg5-deficient and wild-type PTECs were used to further investigate the underlying cellular mechanisms. Results Analysis of human kidney biopsy specimens revealed an increased ferroptotic signature (4-hydroxynonenal immunostaining), impaired autophagy (SQSTM1 accumulation) and AMPK inactivation (reduced p-AMPK) in PTECs of individuals with DKD. In STZ-treated Atg5 knockout (Atg5KO) mice, experiments combining ischaemia–reperfusion injury with ferrostatin-1 treatment showed that autophagy suppressed ferroptotic susceptibility. Additionally, susceptibility to ferroptosis was heightened in db/db mice following ischaemia–reperfusion injury; however, this effect was mitigated by enhancing autophagy through rapamycin treatment. In primary PTECs isolated from Atg5KO mice, ferroptotic cell death and lipid peroxidation were significantly increased, together with elevated mitochondrial reactive oxygen species. Mitochondrial DNA/RNA depletion substantially abolished ferroptotic effects in Atg5KO cells. Furthermore, high-glucose treatment inactivated AMPK and promoted ferroptosis, whereas treatment with the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) attenuated ferroptosis in vitro and reduced vulnerability to AKI in DKD models. Conclusions/interpretation These findings demonstrate that impaired autophagy and inactivated AMPK heighten susceptibility to ferroptosis in DKD, suggesting that therapeutic strategies targeting autophagy and AMPK activation may reduce ferroptosis-associated kidney injury in individuals with diabetes. Graphical Abstract
Funding Information
  • the G-7 Scholarship Foundation
  • Kanae Foundation for the Promotion of Medical Science
  • The Ichiro Kanehara Foundation
  • the Japan Diabetes Foundation
  • the Japan Diabetes Foundation/Costco Wholesale Japan Ltd.
  • Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (23K07671)
  • Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (24K02467)
  • Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (25K19490)
  • MSD Life Science Foundation, Public Interest Incorporated Foundation
  • Japan Diabetes Foundation/Nippon Boehringer Ingelheim Co., Ltd. & Eli Lilly Japan K.K.
  • the Osaka Kidney Bank
  • Uehara Memorial Foundation

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