Abstract
The <i>pdx1</i><sup>-/-</sup> zebrafish mutant was recently established as a novel animal model of diabetic retinopathy. Here, we investigate whether knockout of <i>pdx1</i> also leads to diabetic kidney disease (DKD). <i>pdx1</i><sup>-/-</sup> larvae exhibit several signs of early DKD such as glomerular hypertrophy, impairments in the filtration barrier corresponding to microalbuminuria and glomerular basement membrane (GBM) thickening. Adult <i>pdx1</i><sup>-/-</sup> mutants show progressive GBM thickening in comparison to the larval state. Heterozygous <i>pdx1</i> knockout also leads to glomerular hypertrophy as initial establishment of DKD similar to the <i>pdx1<sup>-/-</sup></i> larvae. RNA sequencing (RNA-seq) of adult <i>pdx1<sup>+/-</sup></i> kidneys uncovered regulations in multiple expected diabetic pathways related to podocyte disruption and hinting at early vascular dysregulation without obvious morphological alterations. Metabolome analysis and pharmacological intervention experiments revealed the contribution of phosphatidylethanolamine (PtdE) in the early establishment of kidney damage. In conclusion, this study identified the <i>pdx1</i> mutant as a novel model for the study of DKD showing signs of the early disease progression already in larval stage and several selective features of later DKD in adult mutants.
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