Glutathione metabolism rewiring protects renal tubule cells against cisplatin-induced apoptosis and ferroptosis

ABSTRACT

Renal proximal tubular cells are highly vulnerable to different types of assaults during filtration and reabsorption, leading to acute renal dysfunction and eventual chronic kidney diseases (CKD). The chemotherapeutic drug cisplatin elicits cytotoxicity causing renal tubular cell death, but its executing mechanisms of action are versatile and elusive. Here, we show that cisplatin induces renal tubular cell apoptosis and ferroptosis by disrupting glutathione (GSH) metabolism. Upon cisplatin treatment, GSH metabolism is impaired leading to GSH depletion as well as the execution of mitochondria-mediated apoptosis and lipid oxidation-related ferroptosis through activating IL6/JAK/STAT3 signaling. Inhibition of JAK/STAT3 signaling reversed cell apoptosis and ferroptosis in response to cisplatin induction. Using a cisplatin-induced acute kidney injury (CAKI) mouse model, we found that inhibition of JAK/STAT3 significantly mitigates cisplatin nephrotoxicity with a reduced level of serum BUN and creatinine as well as proximal tubular distortion. In addition, the GSH booster baicalein also reclaims cisplatin-induced renal tubular cell apoptosis and ferroptosis as well as the in vivo nephrotoxicity. In conclusion, cisplatin disrupts glutathione metabolism, leading to renal tubular cell apoptosis and ferroptosis. Rewiring glutathione metabolism represents a promising strategy for combating cisplatin nephrotoxicity.

KEYWORDS:

• Glutathione metabolism
• renal tubular
• apoptosis
• ferroptosis
• JAK/STAT3
• Cisplatin
• Baicalein
• Acute kidney injury

Acknowledgments

We would like to thank Sebastian A. Liu (Department of Internal Medicine, UC Davis) for manuscript proofreading.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data presented in this study are available upon request from the corresponding author.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (82270713); Key Laboratory Foundation of Structural Deformities in Children of Suzhou (SZS2022018). Gusu Health Talent Project of Suzhou (GSWS2019017, GSWS2019052, and GSWS2020049); Key Disease Project of Suzhou Health Commission (LCZX201908); Natural Science Foundation of Jiangsu Province of China (BK20191176); Suzhou Science and Technology Development Plan [People’s Livelihood Science and Technology] (SYS2019090).