Cisplatin Nephrotoxicity Is Critically Mediated by the Availability of BECLIN1

Area of Science:

• Nephrology
• Molecular Biology
• Cellular Stress Response

Background:

• Cisplatin is a vital chemotherapy drug, but its use is limited by nephrotoxicity.
• The precise mechanisms of cisplatin-induced proximal tubular cell apoptosis remain unclear.
• BECLIN1 (ATG6), an autophagy protein, interacts with BCL2 and may influence apoptosis.

Purpose of the Study:

• To investigate the role of BECLIN1 in cisplatin-induced acute kidney injury (AKI).
• To determine if BECLIN1's protective effect against AKI is linked to autophagy or apoptosis.
• To explore the mechanistic link between BECLIN1 and cisplatin-induced cellular stress.

Main Methods:

• Utilized mice with heterozygous deletion of the Becn1 gene.
• Assessed renal function, autophagy markers, and apoptosis in mice after cisplatin administration.
• Analyzed primary proximal tubular cells from Becn1 heterozygous mice.
• Investigated the impact of ER stress inhibition using tauroursodeoxycholic acid (TUDCA).

Main Results:

• Reduced BECLIN1 levels did not affect baseline renal function or autophagy.
• Becn1 heterozygous mice showed significantly increased susceptibility to cisplatin-induced AKI.
• Nephrotoxicity was directly correlated with proximal tubular BECLIN1 content.
• BECLIN1 deficiency sensitized cells to cisplatin-induced ER stress, not primarily autophagy or apoptosis.
• TUDCA treatment mitigated cisplatin-induced cell death in Becn1 heterozygotes.

Conclusions:

• BECLIN1 plays a critical role in protecting proximal tubular cells against cisplatin-induced ER stress.
• This protective function of BECLIN1 is independent of its role in autophagy.
• Findings reveal a novel therapeutic strategy targeting ER stress pathways for managing cisplatin nephrotoxicity and AKI.