c-Jun Amino Terminal Kinase Signaling Promotes Aristolochic Acid-Induced Acute Kidney Injury.

Area of Science:

• Nephrology
• Toxicology
• Molecular Biology

Background:

• Aristolochic acid (AA) is a nephrotoxin causing DNA damage and kidney disease.
• AA induces pro-fibrotic responses via the c-Jun amino terminal kinase (JNK) pathway in cultured cells.

Purpose of the Study:

• To investigate the in vivo role of JNK signaling in AA-induced acute kidney injury and chronic renal fibrosis.
• To evaluate the therapeutic potential of a JNK inhibitor (CC-930) in mouse models of AA nephrotoxicity.

Main Methods:

• Mouse models of acute high-dose and chronic low-dose AA exposure.
• Administration of a JNK inhibitor (CC-930).
• Assessment of renal function, tubular cell damage, DNA damage response, senescence, macrophage infiltration, and pro-inflammatory markers.

Main Results:

• CC-930 inhibited JNK signaling and protected against acute AA-induced kidney injury, reducing inflammation.
• In chronic AA exposure, CC-930 inhibited JNK but did not prevent renal dysfunction, tubular damage, senescence, or fibrosis.
• Reduced macrophage infiltration and pro-inflammatory response were observed in both acute and chronic models with CC-930 treatment.

Conclusions:

• JNK signaling contributes to acute AA-induced tubular damage, potentially via oxidative stress.
• JNK signaling is not involved in the tubular atrophy and senescence driving chronic kidney disease from sustained AA DNA damage.
• Targeting JNK may be beneficial for acute aristolochic acid nephrotoxicity but not for established chronic disease.