Simultaneous deletion of Bax and Bak is required to prevent apoptosis and interstitial fibrosis in obstructive...

Area of Science:

• Nephrology
• Molecular Biology
• Cell Death Research

Background:

• Proximal tubular injury and apoptosis are central to kidney fibrosis development in chronic kidney disease.
• The precise molecular mechanisms linking tubular apoptosis to kidney fibrosis remain unclear.
• Bcl-2-associated X (Bax) and Bcl-2 antagonist/killer (Bak) are key regulators of intrinsic apoptosis.

Purpose of the Study:

• To investigate the roles of Bax and Bak in the progression of kidney fibrosis.
• To determine if dual deficiency of Bax and Bak can prevent kidney fibrosis.
• To elucidate the molecular pathways involved in Bax/Bak-mediated kidney fibrosis.

Main Methods:

• Utilized a mouse model of unilateral ureteral obstruction (UUO) to induce kidney injury and fibrosis.
• Generated mice with proximal tubule-specific Bax deletion, systemic Bak deletion, and combined Bax/Bak deletion.
• Assessed tubular apoptosis, atrophy, inflammation, fibrogenic cytokine expression, and oxidative stress.

Main Results:

• Dual deficiency of Bax and Bak significantly inhibited tubular apoptosis and atrophy following UUO.
• Combined Bax and Bak ablation suppressed UUO-induced kidney inflammation and fibrosis.
• Individual deletion of Bax or Bak was insufficient to prevent apoptosis, indicating compensatory roles.

Conclusions:

• Dual ablation of Bax and Bak is necessary to effectively prevent tubular apoptosis and subsequent kidney inflammation and fibrosis.
• Targeting both Bax and Bak may represent a therapeutic strategy for chronic kidney disease.
• Bax and Bak play compensatory roles in mediating tubular apoptosis during kidney injury.