Hedgehog pathway negatively regulated depleted uranium-induced nephrotoxicity.

Area of Science:

• Toxicology
• Molecular Biology
• Renal Physiology

Background:

• Depleted uranium (DU) exposure poses significant radiological and chemical toxicity risks, with kidneys being a primary target organ.
• The Hedgehog (Hh) signaling pathway is implicated in tissue injury responses, but its specific role in DU-induced nephrotoxicity remains largely uncharacterized.

Purpose of the Study:

• To investigate the role of Gli2, a critical transcription factor in the Hh pathway, in the pathogenesis of DU-induced nephrotoxicity.
• To evaluate the therapeutic potential of targeting Gli2 for mitigating kidney damage caused by DU exposure.

Main Methods:

• Utilized a conditional knockout mouse model (CK19-positive tubular epithelial cells specific Gli2 KO) exposed to DU.
• Analyzed histopathological changes and Hh signaling pathway activation in kidney tissues.
• Assessed DU-induced cytotoxicity in HEK-293T cells using Gant61 (Hh pathway inhibitor) and Gli2 overexpression.

Main Results:

• DU exposure led to significant nephrotoxicity, characterized by Hh pathway activation.
• Genetic deletion of Gli2 attenuated DU-induced kidney damage and normalized biochemical markers.
• Pharmacological inhibition of Gli1/2 with Gant61 reduced DU cytotoxicity by inhibiting apoptosis and reactive oxygen species (ROS) formation.
• Overexpression of Gli2 exacerbated DU-induced cytotoxicity, increasing apoptosis and ROS levels.

Conclusions:

• The Hh signaling pathway, specifically through Gli2, plays a detrimental role in DU-induced nephrotoxicity.
• Inhibition of Gli2 demonstrates nephroprotective effects against DU exposure.
• Targeting Gli2 represents a promising therapeutic strategy for managing kidney injury resulting from depleted uranium contamination.