Compound C Protects Against Cisplatin-Induced Nephrotoxicity Through Pleiotropic Effects

Area of Science:

• Nephrology
• Molecular Biology
• Pharmacology

Background:

• AICAR (Acadesine/AICA riboside), an AMPK activator, protects against cisplatin-induced renal tubular cell apoptosis.
• Dorsomorphin (compound C), an AMPK inhibitor, also demonstrated protective effects against cisplatin-induced apoptosis, prompting further investigation.

Purpose of the Study:

• To investigate the protective effects of compound C against cisplatin-induced nephrotoxicity.
• To elucidate the specific mechanisms underlying compound C's protective action, particularly its relationship with AMPK, P53, and endoplasmic reticulum (ER) stress.

Main Methods:

• In vitro studies using Boston University mouse proximal tubular cells (BUMPT-306) treated with cisplatin and varying dosages of AICAR or compound C.
• In vitro evaluation of compound C's effect using AMPK-siRNA.
• In vivo studies in male C57BL/6 mice to assess compound C's efficacy against cisplatin-induced nephrotoxicity.

Main Results:

• Both compound C and AICAR reduced renal tubular cell apoptosis in a dose-dependent manner.
• Compound C significantly decreased serum creatinine and attenuated renal tubular injury in cisplatin-treated mice.
• Mechanistically, compound C inhibited P53, CHOP, and p-IREα, and its protective effects were independent of AMPK inhibition.

Conclusions:

• Compound C protects against cisplatin-induced nephrotoxicity through mechanisms independent of AMPK inhibition.
• Compound C exerts its renoprotective effects by inhibiting P53 and alleviating endoplasmic reticulum (ER) stress.
• Compound C exhibits pleiotropic effects that may be beneficial in mitigating cisplatin-induced kidney damage.