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Published on: March 11, 2016
Sinapic acid modulates Nrf2/HO-1 signaling pathway in cisplatin-induced nephrotoxicity in rats
1Department of Pharmacology & Toxicology College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia.
Background:
Cisplatin-induced nephrotoxicity is related to increased reactive oxygen species and inflammatory cytokines in the kidney. Sinapic acid (SA) has both antioxidant and anti-inflammatory activities.
Aims:
We determined the effects of SA on cisplatin-induced nephrotoxicity in rats, and the potential mechanisms by which it augments antioxidant responses and attenuates nephrotoxicity related to oxidative/nitrosative stress, apoptosis, and inflammation.
Methods:
Kidney function markers (i.e., serum urea, uric acid, creatinine, and lactate dehydrogenase), oxidative stress markers (i.e., lipid peroxidation and nitric oxide), antioxidant systems (i.e., superoxide dismutase, catalase, and reduced glutathione), inflammation markers (i.e., tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6], and myeloperoxidase [MPO]), apoptotic markers (caspase 3, Bax, and Bcl-2), and the levels of nuclear factor-κB (NF-κB [p65]), Nrf2, and heme oxygenase-1 (HO-1) were assessed. Histopathological examinations of the kidney were also used to evaluate cisplatin-induced nephrotoxicity.
Key Findings:
SA (10 and 20mg/kg) pretreatment ameliorated kidney function, upregulated antioxidant levels, and downregulated lipid peroxidation and nitric oxide levels in cisplatin-injected rats, resulting in significant reductions in oxidative stress and replenishment of endogenous antioxidant enzymes. Cisplatin upregulated cytokines (i.e., TNF-α and IL-6) and MPO, increased apoptosis, and downregulated Nrf2 and HO-1. SA pretreatment downregulated the pro-apoptotic caspase-3 and Bax proteins, and upregulated the anti-apoptotic Bcl-2 protein. SA pretreatment also alleviated the extent of histological impairment and reduced neutrophil infiltration in renal tubules.
Significance:
The results suggest that the Nrf2/HO-1 signaling pathway may be the primary target for protection from cisplatin-induced nephrotoxicity by SA, and that SA reduces oxidative stress, inflammation, and apoptosis by inhibiting NF-κB.
Insights
Sinapic acid (SA) protects against cisplatin-induced kidney damage by reducing oxidative stress, inflammation, and apoptosis. SA activates the Nrf2/HO-1 pathway and inhibits NF-κB, preserving kidney function.
Area of Science:
- Nephrology
- Pharmacology
- Toxicology
Background:
- Cisplatin chemotherapy can cause kidney damage due to increased oxidative stress and inflammation.
- Sinapic acid (SA) possesses antioxidant and anti-inflammatory properties that may counteract these effects.
Purpose of the Study:
- To investigate the protective effects of sinapic acid (SA) against cisplatin-induced nephrotoxicity in a rat model.
- To elucidate the underlying mechanisms involving oxidative stress, apoptosis, and inflammation.
Main Methods:
- Rats were pretreated with SA before cisplatin injection.
- Evaluated kidney function markers, oxidative stress, antioxidant enzymes, inflammatory cytokines, and apoptosis markers.
- Assessed levels of key signaling proteins like Nrf2, HO-1, and NF-κB.
- Histopathological examination of kidney tissues was performed.
Main Results:
- SA pretreatment significantly improved kidney function and reduced markers of oxidative stress and inflammation in cisplatin-treated rats.
- SA upregulated endogenous antioxidant systems and downregulated pro-inflammatory and pro-apoptotic markers.
- SA treatment modulated the Nrf2/HO-1 and NF-κB signaling pathways, reducing cisplatin-induced kidney damage and neutrophil infiltration.
Conclusions:
- Sinapic acid demonstrates significant nephroprotective effects against cisplatin toxicity in rats.
- The protective mechanisms involve the activation of the Nrf2/HO-1 pathway and inhibition of NF-κB, thereby reducing oxidative stress, inflammation, and apoptosis.
