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Elevated MG-H1 in glo1-/-aldh3a1-/- zebrafish caused microvasculature alterations and glucose metabolism impairment via decreased proteasome activity

ABSTRACT: Dicarbonyl stress is characterized by the abnormal accumulation of dicarbonyl reactive metabolites, leading to increased modification of proteins, DNA and lipids, thereby contributing to cellular and tissue dysfunction in diabetes, diabetic complications and other diseases. glo1 knockout zebrafish exhibited moderately increased MG levels, yet this was inadequate to induce trunk vessels alterations due to elevated ALDH activity and mRNA expression levels, which partially act as compensatory mechanism. Excess 4-HNE induced pancreas dysfunction in aldh3a1 knockout zebrafish larvae, inhibiting insulin expression and thereby facilitating hyperglycemia and hyaloid vasculature alterations. To evaluate the combined function of Glo1 and Aldh3a1 in glucose homeostasis and diabetic microvasculature, glo1-/-aldh3a1-/- zebrafish were generated using CRISPR/Cas9 technology. Multiple experiments are performed regarding vasculature alterations, glucose homeostasis, transcriptome, and metabolomics in Tg(fli1:EGFP) zebrafish. glo1-/-aldh3a1-/- zebrafish larvae displayed angiogenic hyaloid vasculature caused by the elevated MG-H1 and decreased proteasomal chymotrypsin-like activity, which could be rescued by the MG-H1 scavenger L-carnosine and proteasome activator Betulinic acid treatments. In adult glo1-/-aldh3a1-/- zebrafish, impaired glucose metabolism, angiogenic retina vasculature and thickened GBM were observed. Thus, our data suggested that an important upstream factor contributing to these phenomena in the context of lacking glo1 and aldh3a1 is MG-H1, possibly through reduced proteasome activity.

ORGANISM(S): Danio rerio

PROVIDER: GSE270442 | GEO | 2024/07/01

REPOSITORIES: GEO

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