Reduced Acrolein Detoxification in akr1a1a Zebrafish Mutants Causes Impaired Insulin Receptor Signaling and Microvascular Alterations.

Autor: Qi H; Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, 68167, Germany.; Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China., Schmöhl F; Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, 68167, Germany., Li X; Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, 68167, Germany., Qian X; Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, 68167, Germany., Tabler CT; Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, 68167, Germany., Bennewitz K; Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, 68167, Germany., Sticht C; NGS Core Facility, Medical Faculty Mannheim, Heidelberg University, Mannheim, 68167, Germany., Morgenstern J; Department of Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, Heidelberg, 69120, Germany.; German Center for Diabetes Research (DZD), Neuherberg, 85764, Germany., Fleming T; Department of Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, Heidelberg, 69120, Germany.; German Center for Diabetes Research (DZD), Neuherberg, 85764, Germany., Volk N; Tissue Bank of the National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University, Heidelberg, 69120, Germany., Hausser I; Institute of Pathology IPH, EM Lab, Heidelberg University Hospital, Heidelberg, 69120, Germany., Heidenreich E; Metabolomics Core Technology Platform, Centre for Organismal Studies, Heidelberg University, Heidelberg, 69120, Germany., Hell R; Metabolomics Core Technology Platform, Centre for Organismal Studies, Heidelberg University, Heidelberg, 69120, Germany., Nawroth PP; Department of Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, Heidelberg, 69120, Germany.; German Center for Diabetes Research (DZD), Neuherberg, 85764, Germany.; Joint Heidelberg-IDC Translational Diabetes Program, Helmholtz-Zentrum, Neuherberg, 85764, Germany., Kroll J; Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, 68167, Germany.
Jazyk: angličtina
Zdroj: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2021 Sep; Vol. 8 (18), pp. e2101281. Date of Electronic Publication: 2021 Jul 18.
DOI: 10.1002/advs.202101281
Abstrakt: Increased acrolein (ACR), a toxic metabolite derived from energy consumption, is associated with diabetes and its complications. However, the molecular mechanisms are mostly unknown, and a suitable animal model with internal increased ACR does not exist for in vivo studying so far. Several enzyme systems are responsible for acrolein detoxification, such as Aldehyde Dehydrogenase (ALDH), Aldo-Keto Reductase (AKR), and Glutathione S-Transferase (GST). To evaluate the function of ACR in glucose homeostasis and diabetes, akr1a1a -/- zebrafish mutants are generated using CRISPR/Cas9 technology. Accumulated endogenous acrolein is confirmed in akr1a1a -/- larvae and livers of adults. Moreover, a series of experiments are performed regarding organic alterations, the glucose homeostasis, transcriptome, and metabolomics in Tg(fli1:EGFP) zebrafish. Akr1a1a -/- larvae display impaired glucose homeostasis and angiogenic retina hyaloid vasculature, which are caused by reduced acrolein detoxification ability and increased internal ACR concentration. The effects of acrolein on hyaloid vasculature can be reversed by acrolein-scavenger l-carnosine treatment. In adult akr1a1a -/- mutants, impaired glucose tolerance accompanied by angiogenic retina vessels and glomerular basement membrane thickening, consistent with an early pathological appearance in diabetic retinopathy and nephropathy, are observed. Thus, the data strongly suggest impaired ACR detoxification and elevated ACR concentration as biomarkers and inducers for diabetes and diabetic complications.
(© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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