title: Simultaneous deletion of Bax and Bak is required to prevent apoptosis and interstitial fibrosis in obstructive nephropathy.
abstract: Proximal tubular injury and apoptosis are key mediators of the development of kidney fibrosis, a hallmark of chronic kidney disease. However, the molecular mechanism by which tubular apoptotic cell death leads to kidney fibrosis is poorly understood. In the present study, we tested the roles of Bcl-2-associated X (Bax) and Bcl-2 antagonist/killer (Bak), two crucial proteins involved in intrinsic apoptotic cell death, in the progression of kidney fibrosis. Mice with proximal tubule-specific Bax deletion, systemic deletion of Bak, and dual deletion of Bax and Bak were subjected to unilateral ureteral obstruction (UUO). Dual deficiency of Bax and Bak inhibited tubular apoptosis and atrophy. Consistent with decreased tubular injury, dual ablation of Bax and Bak suppressed UUO-induced inflammation and kidney fibrosis with decreased tubular cell cycle arrest, expression of fibrogenic and inflammatory cytokines, and oxidative stress in the kidney. Bax or Bak deficiency was insufficient to prevent apoptosis and all other aforementioned malevolent effects, suggesting compensatory mediation by each other in the respective signaling pathways. These data suggest that dual ablation of Bax and Bak in the kidney is required to prevent UUO-induced tubular apoptosis and the consequent kidney inflammation and fibrosis.
authors.affiliation: Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska; and.
authors.forename: Hee-Seong
authors.initials: HS
authors.lastname: Jang
authors.affiliation: Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska; and Department of Internal Medicine, Section of Nephrology, University of Nebraska Medical Center, Omaha, Nebraska bpadanilam@unmc.edu.
authors.forename: Babu J
authors.initials: BJ
authors.lastname: Padanilam
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D003094:Collagen / Q000378:metabolism; D005355:Fibrosis; D017353:Gene Deletion; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000235:genetics* / Q000473:pathology*; D007684:Kidney Tubules / Q000473:pathology; D015227:Lipid Peroxidation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014517:Ureteral Obstruction / Q000473:pathology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics*; D051028:bcl-2-Associated X Protein / Q000235:genetics*
chemical_list: D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D003094:Collagen
keywords: Bcl-2 antagonist/killer; Bcl-2-associated X; apoptosis; chronic kidney disease; fibrosis; inflammation; oxidative stress