Related Experiment Videos
Protective effect of cyclic AMP against cisplatin-induced nephrotoxicity.
Kazuto Mishima1, Anri Baba, Misaki Matsuo
1Department of Pharmacy, Kyushu University Hospital 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Free Radical Biology & Medicine
|April 25, 2006
Summary
Cyclic AMP protects kidney cells from cisplatin damage by reducing oxidative stress and tumor necrosis factor-alpha (TNF-alpha) production. This protective effect involves blocking p38 mitogen-activated protein kinase (MAPK) activation, suggesting a novel therapeutic target for acute kidney injury.
Area of Science:
- Nephrology
- Cell Biology
- Pharmacology
Background:
- Reactive oxygen species (ROS) contribute to cisplatin-induced necrotic kidney injury.
- Apoptosis from continuous low-dose cisplatin exposure is ROS-independent.
- Cyclic AMP (cAMP) signaling pathways are explored for cytoprotective effects.
Purpose of the Study:
- To investigate the protective role of cyclic AMP (cAMP) against cisplatin-induced renal tubular cell necrosis and acute renal failure.
- To elucidate the intracellular mechanisms underlying cAMP-mediated protection.
Main Methods:
- Utilized cultured renal tubular cells and an in vivo rat model of cisplatin-induced acute renal failure.
- Administered cAMP-stimulating agents (dibutyryl cAMP, forskolin, beraprost) and p38 MAPK inhibitors (SB203580, PD169316).
- Assessed markers of oxidative stress (lipid peroxidation, superoxide dismutase activity), TNF-alpha levels, and p38 MAPK phosphorylation.
Main Results:
- cAMP-stimulating agents and antioxidants (N-acetylcysteine, glutathione) protected against cisplatin-induced cell injury and lipid peroxidation.
- Cisplatin increased TNF-alpha and phosphorylated p38 MAPK, which were attenuated by cAMP analogues and p38 MAPK inhibitors.
- In vivo, cisplatin-induced renal injury and elevated renal TNF-alpha were reversed by N-acetylcysteine and beraprost.
Conclusions:
- Cyclic AMP confers protection against cisplatin-induced renal oxidative injury.
- Protection is mediated by reducing ROS and inhibiting TNF-alpha synthesis via p38 MAPK pathway blockade.
- Targeting cAMP signaling represents a potential therapeutic strategy for cisplatin nephrotoxicity.