Impaired detoxification of Acrolein interrupted ocular vascular integrity and kidney structure in akr7a3-/- zebrafish via enhancing Arachidonic acid/leukotriene metabolism

Acrolein (ACR) is an endogenous reactive unsaturated aldehyde that can be detoxified by the aldo-keto reductase (AKR) enzyme system. The accumulation of ACR is associated with several health issues, including inflammation, oxidative stress, and cardiovascular diseases. In this study, an akr7a3 mutant zebrafish with the Tg(fli1: EGFP) signature was generated to investigate the effect of ACR on vascular integrity. Elevated ACR levels were observed in akr7a3-/- zebrafish larvae and adults. Subsequent experiments demonstrated that increased ACR induced an enlargement of the hyaloid and retinal vasculature, as well as alterations in the larvae pronephron and adult kidney. Transcriptome and metabolomics analyses, followed by validation experiments, revealed that the upregulation of arachidonic acid metabolism and leukotriene production are responsible for the observed vascular and organ changes. In conclusion, our data suggests that the loss of akr7a3 in zebrafish impairs the detoxification of ACR, which subsequently disrupts vascular integrity and normal kidney structure by promoting an inflammatory response. Overall design: akr7a3-/-zebrafish were generated using CRISPR/Cas9 technology. Multiple experiments are performed regarding vasculature alterations, transcriptome, and metabolomics in Tg(fli1:EGFP) zebrafish.