UNC5B receptor deletion exacerbates tissue injury in response to AKI

Area of Science:

• Molecular Biology
• Cell Biology
• Nephrology

Background:

• Netrin-1 signaling, through receptors like UNC5B, influences cell survival and apoptosis.
• The in vivo function of UNC5B in cell survival during cellular stress and tissue injury remains largely uncharacterized.

Purpose of the Study:

• To investigate the role of UNC5B in kidney epithelial cell survival under conditions of acute kidney injury (AKI).
• To elucidate the molecular mechanisms by which UNC5B affects cell death pathways, including p53 and Akt signaling.

Main Methods:

• Utilized genetically modified mice with targeted deletion of UNC5B in kidney epithelial cells (UNC5B(-/flox/GGT-cre)) and control littermates.
• Employed two distinct models of AKI: ischemia-reperfusion injury and cisplatin-induced nephrotoxicity.
• Assessed renal function, histology, tubular apoptosis, p53 activation, inflammation, and performed in vitro studies using cultured tubular epithelial cells.

Main Results:

• UNC5B-deficient mice exhibited significantly impaired renal function and increased kidney damage following AKI compared to controls.
• Loss of UNC5B led to increased tubular apoptosis, heightened p53 activation, and exacerbated inflammation post-injury.
• In vitro, UNC5B suppression enhanced cisplatin-induced cell death in a p53-dependent manner and reduced Akt phosphorylation, while UNC5B overexpression conferred protection.

Conclusions:

• The netrin-1 receptor UNC5B is essential for maintaining kidney cell survival during acute kidney injury.
• UNC5B promotes cell survival by facilitating Akt-mediated inactivation of p53 in response to cellular stress.
• Targeting the UNC5B pathway may offer therapeutic potential for mitigating kidney injury.