JNK and Jag1/Notch2 co-regulate CXCL16 to facilitate cypermethrin-induced kidney damage

Area of Science:

• Toxicology
• Molecular Biology
• Renal Pathology

Background:

• Cypermethrin (CYP) is a pyrethroid pesticide with known nephrotoxic potential.
• The molecular mechanisms underlying CYP-induced kidney damage, including the roles of specific signaling pathways and microRNAs, require further elucidation.

Purpose of the Study:

• To investigate the roles of the MAPK pathway, Jag/Notch pathway, and microRNAs in cypermethrin-induced nephrotoxicity.
• To elucidate the signaling cascades involved in CYP-mediated renal inflammation and damage.

Main Methods:

• Utilized Sprague-Dawley rats and glomerular mesangial cells exposed to β-cypermethrin.
• Analyzed renal histomorphology, DNA damage, renal function markers (Cys-C, β2-Mg), oxidative stress (ROS), miRNA expression (miR-21-5p), and key pathway proteins (JNK, c-Jun, Jag1, Notch2, Hes1, CXCL16).
• Employed techniques including inhibitor treatments, gene/protein overexpression, Co-IP, ChIP, and gene silencing to confirm pathway interactions.

Main Results:

• β-cypermethrin induced significant renal histopathological alterations, DNA damage, and impaired renal function.
• Activated the JNK/c-Jun pathway via ROS and oxidative stress, and altered miRNA expression, notably increasing miR-21-5p.
• miR-21-5p directly targeted and downregulated the Jag1/Notch2/Hes1 pathway. β-CYP induced CXCL16, leading to inflammation.
• CXCL16 was co-regulated by JNK/c-Jun and Jag1/Notch2/Hes1 pathways, driving renal inflammation.

Conclusions:

• β-cypermethrin exerts nephrotoxicity by directly damaging kidney structures and inducing inflammation.
• CYP-induced renal inflammation is mediated by CXCL16, which is co-regulated by the JNK/c-Jun and Jag1/Notch2/Hes1 pathways, ultimately contributing to kidney damage.