Reactive carbonyl species (RCS) are spontaneously formed in the metabolism and modify and impair the function of DNA, proteins and lipids leading to several organ complications. In zebrafish, knockout of the RCS detoxifying enzymes glyoxalase 1 (Glo 1), aldehyde dehydrogenase 3a1 (Aldh3a1) and aldo-ketoreductase 1a1a (Akr1a1a) showed a signature of elevated RCS which specifically regulated glucose metabolism, hyperglycemia and diabetic organ damage. aldh2.1 was compensatory upregulated in glo1 −/− animals and therefore this study aimed to investigate the detoxification ability for RCS by Aldh2.1 in zebrafish independent of ethanol exposure. aldh2.1 knockout zebrafish were generated using CRISPR/Cas9 and subsequently analyzed on a histological, metabolomic and transcriptomic level. aldh2.1 −/− zebrafish displayed increased endogenous acetaldehyde (AA) inducing an increased angiogenesis in retinal vasculature. Expression and pharmacological interventional studies identified an imbalance of c -Jun N-terminal kinase (JNK) and p38 MAPK induced by AA, which mediate an activation of angiogenesis. Moreover, increased AA in aldh2.1 −/− zebrafish did not induce hyperglycemia, instead AA inhibited the expression of glucokinase ( gck) and glucose-6-phosphatase ( g6pc) , which led to an impaired glucose metabolism. In conclusion, the data have identified AA as the preferred substrate for Aldh2.1's detoxification ability, which subsequently causes microvascular organ damage and impaired glucose metabolism.

Diabetic retinopathy is one of the most important microvascular complications associated with diabetes mellitus, and a leading cause of vision loss or blindness worldwide. Hyperglycaemic conditions disrupt microvascular integrity at the level of the neurovascular unit. In recent years, zebrafish (Danio rerio) have come into focus as a model organism for various metabolic diseases such as diabetes. In both mammals and vertebrates, the anatomy and the function of the retina and the neurovascular unit have been highly conserved. In this review, we focus on the advances that have been made through studying pathologies associated with retinopathy in zebrafish models of diabetes. We discuss the different cell types that form the neurovascular unit, their role in diabetic retinopathy and how to study them in zebrafish. We then present new insights gained through zebrafish studies. The advantages of using zebrafish for diabetic retinopathy are summarised, including the fact that the zebrafish has, so far, provided the only animal model in which hyperglycaemia-induced retinal angiogenesis can be observed. Based on currently available data, we propose potential investigations that could advance the field further.

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