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3-MCPD 1-Palmitate Induced Tubular Cell Apoptosis In Vivo via JNK/p53 Pathways
Man Liu1, Guoren Huang2, Thomas T Y Wang3
1*Institute of Food and Nutraceutical Science, School of Agriculture & Biology, Shanghai Jiao Tong University, Shanghai 200240, China Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing Technology & Business University (BTBU), Beijing 100048, China.
Abstract:
Fatty acid esters of 3-chloro-1, 2-propanediol (3-MCPD esters) are a group of processing induced food contaminants with nephrotoxicity but the molecular mechanism(s) remains unclear. This study investigated whether and how the JNK/p53 pathway may play a role in the nephrotoxic effect of 3-MCPD esters using 3-MCPD 1-palmitate (MPE) as a probe compound in Sprague Dawley rats. Microarray analysis of the kidney from the Sprague Dawley rats treated with MPE, using Gene Ontology categories and KEGG pathways, revealed that MPE altered mRNA expressions of the genes involved in the mitogen-activated protein kinase (JNK and ERK), p53, and apoptotic signal transduction pathways. The changes in the mRNA expressions were confirmed by qRT-PCR and Western blot analyses and were consistent with the induction of tubular cell apoptosis as determined by histopathological, TUNEL, and immunohistochemistry analyses in the kidneys of the Sprague Dawley rats. Additionally, p53 knockout attenuated the apoptosis, and the apoptosis-related protein bax expression and cleaved caspase-3 activation induced by MPE in the p53 knockout C57BL/6 mice, whereas JNK inhibitor SP600125 but not ERK inhibitor U0126 inhibited MPE-induced apoptosis, supporting the conclusion that JNK/p53 might play a critical role in the tubular cell apoptosis induced by MPE and other 3-MCPD fatty acid esters.
Insights
3-MCPD esters, food contaminants, induce kidney toxicity by activating the JNK/p53 pathway, leading to tubular cell apoptosis. This pathway is crucial for the observed nephrotoxicity.
Area of Science:
- Toxicology
- Molecular Biology
- Food Safety
Background:
- 3-chloro-1,2-propanediol (3-MCPD) esters are food processing contaminants.
- Their nephrotoxicity is established, but the underlying molecular mechanisms are unclear.
Purpose of the Study:
- To investigate the role of the JNK/p53 pathway in 3-MCPD ester-induced nephrotoxicity.
- To elucidate the molecular mechanisms of kidney damage caused by 3-MCPD esters.
Main Methods:
- Sprague Dawley rats were treated with 3-MCPD 1-palmitate (MPE).
- Kidney gene expression was analyzed using microarray, qRT-PCR, and Western blot.
- Apoptosis was assessed via histopathology, TUNEL, and immunohistochemistry.
- p53 knockout and JNK/ERK inhibitors were used to confirm pathway involvement.
Main Results:
- MPE altered mRNA expression of genes in JNK, ERK, p53, and apoptotic pathways.
- These changes correlated with induced tubular cell apoptosis in rat kidneys.
- p53 knockout attenuated MPE-induced apoptosis and related protein expression.
- JNK inhibition, but not ERK inhibition, reduced MPE-induced apoptosis.
Conclusions:
- The JNK/p53 pathway plays a critical role in 3-MCPD ester-induced tubular cell apoptosis.
- This pathway is a key mediator of the nephrotoxicity associated with 3-MCPD esters and related compounds.
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