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Tanshinone IIA prevents acetaminophen-induced nephrotoxicity through the activation of the Nrf2-Mrp2/4 pathway in
Xiqian Zhang1,2, Fangyi Long3, Ruina Li4
1Department of Pharmacy, The Third People's Hospital of Chengdu & College of Medicine, Southwest Jiaotong University, Chengdu, China.
Abstract:
It's known that APAP overdose often leads to hepatotoxicity and nephrotoxicity. In the present study, we investigated the preventative effect of Tan IIA on APAP-induced nephrotoxicity. Mice were orally administrated with Tan IIA (10 or 30 mg/kg/day) for 1 week and subsequently gavaged with 200 mg/kg of APAP. Tan IIA reduced APAP-induced nephrotoxicity as evidenced by histopathological evaluation and serum creatinine levels. Tan IIA pretreatment promoted the efflux of the toxic intermediate metabolite N-acetyl-p-benzoquinone imine (NAPQI), thus reduced its injury to mouse kidney. After Tan IIA pretreatment, a remarkable increase in mRNA and protein expression of Nrf2 and its target genes Mrp2 and Mrp4 was observed in Nrf2+/+ mice kidneys, however, no obvious change of Mrp2 and Mrp4 mRNA and protein expression was detected in Nrf2-/- mice kidneys. HK-2 cells were used for exploring the roles of Tan IIA in the Nrf2-MRPs pathway in vitro. Consistently, Tan IIA up-regulated the Nrf2-MRPs pathway and promoted the nuclear Nrf2 accumulation in HK-2 cells. Collectively, our findings suggested that Tan IIA facilitated the clearance of toxic intermediate metabolite NAPQI from the kidney through upregulation of the Nrf2-MRP2/4 pathway, thereby, performing preventive effects against APAP-induced nephrotoxicity.
Insights
Tan IIA protects against acetaminophen-induced kidney damage by enhancing the removal of toxic metabolites. This protection involves the Nrf2-MRP2/4 pathway, crucial for clearing harmful substances from the kidneys.
Area of Science:
- Pharmacology and Toxicology
- Renal Physiology
- Natural Product Chemistry
Background:
- Acetaminophen (APAP) overdose is a common cause of acute liver and kidney injury.
- Understanding protective mechanisms against APAP-induced nephrotoxicity is critical for developing therapeutic strategies.
- Tan IIA, a natural compound, has shown potential in various biological activities.
Purpose of the Study:
- To investigate the preventative effects of Tan IIA against APAP-induced nephrotoxicity in a mouse model.
- To elucidate the underlying molecular mechanisms, focusing on the Nrf2-MRPs pathway.
Main Methods:
- Mice were pretreated with Tan IIA before APAP administration.
- Histopathological evaluation and serum creatinine levels were assessed to determine nephrotoxicity.
- mRNA and protein expression of Nrf2 and its target genes (Mrp2, Mrp4) were analyzed in kidney tissues and HK-2 cells.
- Experiments were conducted in both wild-type and Nrf2-knockout mice to confirm the role of Nrf2.
Main Results:
- Tan IIA pretreatment significantly reduced APAP-induced kidney damage.
- Tan IIA promoted the efflux of the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI).
- Tan IIA upregulated the expression of Nrf2 and its target genes Mrp2 and Mrp4 in a Nrf2-dependent manner.
- In vitro studies confirmed Tan IIA's role in activating the Nrf2-MRPs pathway in HK-2 cells.
Conclusions:
- Tan IIA exerts a protective effect against APAP-induced nephrotoxicity.
- The mechanism involves the facilitation of toxic metabolite (NAPQI) clearance via the Nrf2-MRP2/4 pathway.
- Tan IIA represents a potential therapeutic agent for preventing acetaminophen-induced kidney injury.
