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Published on: January 7, 2013
Stevia and stevioside protect against cisplatin nephrotoxicity through inhibition of ERK1/2, STAT3, and NF-κB
Iva Potočnjak1, Dalibor Broznić1, Marija Kindl2
1Department of Chemistry and Biochemistry, Faculty of Medicine, University of Rijeka, Rijeka, Croatia.
Abstract:
We investigated the effect of natural sweetener Stevia rebaudiana and its constituent stevioside in cisplatin (CP)-induced kidney injury. Male BALB/cN mice were orally administered 10, 20, and 50 mg/kg body weight of Stevia rebaudiana ethanol extract (SE) or stevioside 50 mg/kg, 48 h after intraperitoneal administration of CP (13 mg/kg). Two days later, CP treatment resulted in histopathological changes showing kidney injury. Increased expression of 4-hydroxynonenal (4-HNE), 3-nitrotyrosine (3-NT), and heme oxygenase-1 (HO-1) in mice kidneys suggested oxidative stress. CP treatment also increased renal expression of nuclear factor-kappaB (NF-κB) p65 subunit and phosphorylated inhibitor of NF-κB (IκBα), as well as expression of pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α). Induction of apoptosis and inhibition of the cell cycle in kidneys was evidenced by increased expression of p53, Bax, caspase-9, and p21, proteolytic cleavage of poly (ADP-ribose) polymerase (PARP), with concomitant suppression of Bcl-2 and cyclin D1 expression. The number of apoptotic cells in kidneys was also assessed. CP administration resulted in activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3). Both SE and stevioside attenuated CP nephrotoxicity by suppressing oxidative stress, inflammation, and apoptosis through mechanism involving ERK1/2, STAT3, and NF-κB suppression.
Insights
Stevia rebaudiana extract and stevioside protect against cisplatin-induced kidney injury by reducing oxidative stress, inflammation, and apoptosis. These natural compounds offer a potential therapeutic strategy for nephrotoxicity.
Area of Science:
- Pharmacology
- Toxicology
- Natural Products Chemistry
Background:
- Cisplatin (CP) is a widely used chemotherapy agent with significant nephrotoxicity.
- Oxidative stress, inflammation, and apoptosis are key mechanisms underlying CP-induced kidney injury.
- Natural compounds are being explored for their protective effects against drug-induced organ damage.
Purpose of the Study:
- To investigate the protective effects of Stevia rebaudiana ethanol extract (SE) and its constituent stevioside against cisplatin-induced nephrotoxicity in mice.
- To elucidate the underlying mechanisms of action, focusing on oxidative stress, inflammation, apoptosis, and key signaling pathways.
Main Methods:
- Male BALB/cN mice were treated with cisplatin (CP) to induce kidney injury.
- Mice received oral administration of Stevia rebaudiana ethanol extract (SE) or stevioside.
- Kidney tissues were analyzed for histopathological changes, oxidative stress markers (4-HNE, 3-NT, HO-1), inflammatory markers (NF-κB, TNF-α), apoptosis markers (p53, Bax, caspase-9, p21, Bcl-2, PARP, cyclin D1), and signaling pathways (ERK1/2, STAT3).
Main Results:
- CP administration induced significant kidney injury, characterized by increased oxidative stress, inflammation, and apoptosis.
- SE and stevioside treatment attenuated CP-induced nephrotoxicity.
- Protective effects were associated with suppressed oxidative stress, reduced inflammation, and decreased apoptosis.
- Mechanistically, SE and stevioside suppressed the activation of NF-κB, ERK1/2, and STAT3 signaling pathways.
Conclusions:
- Stevia rebaudiana extract and stevioside demonstrate significant nephroprotective effects against cisplatin-induced kidney injury.
- These natural compounds mitigate kidney damage by inhibiting oxidative stress, inflammation, and apoptosis.
- The findings suggest that SE and stevioside hold therapeutic potential for preventing or treating chemotherapy-induced nephrotoxicity.
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