pdx1 Knockout Leads to a Diabetic Nephropathy-Like Phenotype in Zebrafish and Identifies Phosphatidylethanolamine as Metabolite Promoting Early Diabetic Kidney Damage

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.

High glucose promotes podocyte movement: From the perspective of single cell motility assay

“…While, how podocyte injury induced by diabetic stimuli resulting in proteinuria is not fully elucidated. Growing evidence demonstrates that podocytes detachment from the glomerular basement membrane after apoptosis is a critical factor in causing proteinuria (Gao et al, 2019; Wiggenhauser et al, 2022). Some other studies have demonstrated that proteinuria occurs before podocyte detachment and apoptosis (M. K. Kang et al, 2020), arguing for potential roles of the epithelial‐to‐mesenchymal transition (EMT) of podocyte in the generation of proteinuria.…”