PUBLICATION

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

Authors

Wiggenhauser, L.M., Metzger, L., Bennewitz, K., Soleymani, S., Boger, M., Tabler, C.T., Hausser, I., Sticht, C., Wohlfart, P., Volk, N., Heidenreich, E., Buettner, M., Hammes, H.P., Kroll, J.

ID

ZDB-PUB-220202-28

Date

2022

Source

Diabetes.. 71(5): 1073-1080 (Journal)

Registered Authors

Kroll, Jens

Keywords

none

Datasets

GEO:GSE179104

MeSH Terms

Male
Phenotype
Hypertrophy/metabolism
Diabetes Mellitus*/metabolism
Humans
Phosphatidylethanolamines
Podocytes*/metabolism
Zebrafish
Female
Diabetic Nephropathies*/metabolism
Animals
Glomerular Basement Membrane

(all 12)

PubMed

35100334 Full text @ Diabetes

Abstract

The pdx1-/- zebrafish mutant was recently established as a novel animal model of diabetic retinopathy. Here, we investigate whether knockout of pdx1 also leads to diabetic kidney disease (DKD). pdx1-/- 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 pdx1-/- mutants show progressive GBM thickening in comparison to the larval state. Heterozygous pdx1 knockout also leads to glomerular hypertrophy as initial establishment of DKD similar to the pdx1-/- larvae. RNA sequencing (RNA-seq) of adult pdx1+/- 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 pdx1 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.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
EGFP	li1Tg	standard conditions	Long-pec	pronephric glomerulus	IFL	Fig. 1
EGFP	li1Tg	standard conditions	Long-pec	pronephric tubule	IFL	Fig. 1
EGFP	pdx1^uh10/+; li1Tg	standard conditions	Long-pec	pronephric glomerulus	IFL	Fig. 1
EGFP	pdx1^uh10/+; li1Tg	standard conditions	Long-pec	pronephric tubule	IFL	Fig. 1
EGFP	pdx1^uh10/+; y1Tg	standard conditions	Adult	kidney vasculature	IFL	Fig. 3
EGFP	pdx1^uh10/uh10; li1Tg	standard conditions	Long-pec	pronephric glomerulus	IFL	Fig. 1
EGFP	pdx1^uh10/uh10; li1Tg	standard conditions	Long-pec	pronephric tubule	IFL	Fig. 1
EGFP	y1Tg	standard conditions	Adult	kidney vasculature	IFL	Fig. 3

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
li1Tg	control	Long-pec	pronephric glomerulus normal length, normal	Fig. 4
li1Tg	control	Long-pec	pronephric glomerulus normal width, normal	Fig. 4
li1Tg	control	Long-pec	pronephric tubule normal length, normal	Fig. 4
li1Tg	chemical treatment by environment: N-(p-amylcinnamoyl)anthranilic acid	Long-pec	pronephric glomerulus decreased width, abnormal	Fig. 4
li1Tg	chemical treatment by environment: N-(p-amylcinnamoyl)anthranilic acid	Long-pec	pronephric glomerulus normal length, normal	Fig. 4
li1Tg	chemical treatment by environment: N-(p-amylcinnamoyl)anthranilic acid	Long-pec	pronephric tubule decreased length, abnormal	Fig. 4
li1Tg	chemical treatment by environment: Meclizine	Long-pec	pronephric glomerulus normal length, normal	Fig. 4
li1Tg	chemical treatment by environment: Meclizine	Long-pec	pronephric glomerulus normal width, normal	Fig. 4
li1Tg	chemical treatment by environment: Meclizine	Long-pec	pronephric tubule normal length, normal	Fig. 4
li1Tg	chemical treatment by injection: phosphatidylethanolamine	Long-pec	glomerular basement membrane increased thickness, abnormal	Fig. 4

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
li1Tg	Tg(wt1b:EGFP)	Transgenic Insertion
uh10		Insertion	pdx1
y1Tg	Tg(fli1:EGFP)	Transgenic Insertion

Human Disease / Model

Sequence Targeting Reagents

Fish

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP

Mapping

Wiggenhauser et al., 2022 ZDB-PUB-220202-28 PMID:35100334

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

Wiggenhauser et al., 2022

ZDB-PUB-220202-28
PMID:35100334