Acrolein is a colorless liquid that has a pungent smell and is used as an intermediate in the production of acrylic acid. Acrolein is an electrophilic compound and quite reactive hence its high toxicity. The toxicological effects of Acrolein have been studied in rats by looking at the cyclophosphamide-derived Acrolein isolated from their kidney. Research studies show the protective action of the low molecular thiols in the kidney cause cellular toxicity. The exposure of rats to Acrolein results in reduced levels of ascorbic acid, glutathione, and α-tocopherol. On a cellular level, Acrolein exposure has diverse effects, including protein abduction, oxidative stress and membrane damage (Tamargo-Gómez, Isaac, and Guillermo 78). It enhances lipid peroxidation, which caused extensive damage to the rat’s kidney indicated by the elevated levels of the biochemical markers. This paper seeks to address the role of Beclin 1, Nrf2 and, PPAR gamma in the reducing Acrolein toxicity of rat kidney.

Beclin 1

Beclin 1 is an essential component and regulator of phosphatidylinositol 3-kinase (PI3K-III) which plays an imperative role in membrane trafficking and the restructuring of the kidney. It modulates the lipid kinase activity of P13K-III by enabling the recruitment of autophagy proteins. Autophagy is termed as cellular clearance mechanism that helps to maintain cellular survival. After a rat is exposed to Acrolein, the serum levels of Beclin which is a crucial regulator autophagy reduce as they try to reduce the toxic levels. Beclin 1 Autophagy induced in response to nutrient deprivation or maintaining homeostasis by clearing damage proteins.

Since Beclin 1 is a positive regulator of autophagy, it combines with other proteins that help to regulate biological functions such as pathogen infection and kidney failure. Beclin 1 contains BH3 and CCD domains which take part in a variety of cellular functions such as apoptosis and endocytosis (Corona, Juan and Michael 155).  Beclin 1 plays a pivotal role of autophagy in cell homeostasis by inhibiting apoptosis.  Therefore, during Acrolein toxicity, there are low serum levels of Beclin 1 as most of it used to maintain cellular survival and homeostasis.

Nrf2

Nuclear erythroid 2-related factor 2 (Nrf2) regulates antioxidative elements that lead to gene expression. It plays an essential role in the adaptive responses to oxidative stress by interacting with the response element aimed and cytoprotection. The Nrf2 activity is regulated by the oxidative stress molecule KEAP1 which induces proteasomal degradation. Notably, oxidative stress and inflammation are caused by Acrolein toxicity. The oxidative-stress molecules tend to accumulate in the kidney in which the Nrf2 is activated. To prevent the inflammation of the kidney, the Nrf2 regulates the function of the kidney by offering cellular protection via the induction of anti-inflammatory and cytoprotective gene expression. As a central regulator, Nrf2 provides cellular defense through the mediation of antioxidation response.

During Acrolein exposure, rats release high levels of Nrf2 from the cytoplasm where it binds with the actin-binding protein (Smedowski et al., 24). The protein is degraded using the ubiquitin-proteasome pathway upon exposure to the oxidative stress; the phosphorylation of Nrf2 leads to its disassociation from the nucleus. After this dissociation, the Nrf2 combines with antioxidant response agents such as NADH and NQ01 to increase activity in the kidney. The Nrf2 function is positively regulated by the KEAP1 that promotes the degradation of the proteasome molecules under the normal physiological conditions. Therefore, the levels of Nrf2 activity increase during Acrolein toxicity as they reduce oxidation and inflammation of the rat’s kidney.

PPAR Gamma

PPAR gamma is a member of a nuclear receptor that plays a significant role in the regulation of lipid metabolism. PPAR gamma is highly expressed in tissues that have high mitochondrial activity and b-oxidation such as the kidney and liver. In the kidney, they are expressed on the proximal tubules. Upon activation of the protein, PPAR gamma helps to reduce kidney toxicity through a different mechanism such as inhibition of the mesangial cell growth and cytokine production of glomerular cells (Durocher et al., 56). The activation of PPAR gamma also has profibrotic outcomes that promote endothelial cell formation in the kidney glomeruli. It regulates the sodium and water reabsorption by increasing the interstitial fluid volume. Therefore, PPAR gamma plays a major regulatory role in metabolic function and energy homeostasis.

Conclusively, Acrolein exposure has diverse effects, including protein abduction, oxidative stress, and membrane damage. It enhances lipid peroxidation, which caused extensive damage in a rat’s kidney indicated. Beclin 1, Nrf2 and, PPAR gamma are protein regulators that help to regulate the kidney activities through membrane trafficking and restructuring, cellular protection via the induction of anti-inflammatory and cytoprotective gene expression and regulatory role in metabolic functions and energy homeostasis.

Works Cited

Corona, Juan Carlos, and Michael R. Duchen. “PPARγ as a therapeutic target to rescue mitochondrial function in neurological disease.” Free Radical Biology and Medicine 100 (2016): 153-163.

Durocher, Marc, et al. “Inflammatory, regulatory, and autophagy co-expression modules and hub genes underlie the peripheral immune response to human intracerebral hemorrhage.” Journal of neuroinflammation 16.1 (2019): 56.

Smedowski, A., et al. “Nuclear factor‐erythroid 2‐related factor‐2 (Nrf2) and peroxisome proliferator‐activated receptor γ coactivator‐1α (PGC‐1α) regulate proteolysis in cornea.” Acta Ophthalmologica 93 (2015).

Tamargo-Gómez, Isaac, and Guillermo Mariño. “AMPK: Regulation of metabolic dynamics in the context of autophagy.” International journal of molecular sciences 19.12 (2018): 3812.