Journal article
Leucine-Rich Repeat in Polycystin-1 Suppresses Cystogenesis in a Zebrafish (Danio rerio) Model of Autosomal-Dominant Polycystic Kidney Disease
International journal of molecular sciences, Vol.25(5), 2886
03/01/2024
DOI: 10.3390/ijms25052886
PMCID: PMC10932423
PMID: 38474131
Abstract
Mutations of
PKD1
coding for polycystin-1 (PC1) account for most cases of autosomal-dominant polycystic kidney disease (ADPKD). The extracellular region of PC1 contains many evolutionarily conserved domains for ligand interactions. Among these are the leucine-rich repeats (LRRs) in the far N-terminus of PC1. Using zebrafish (
Danio rerio
) as an in vivo model system, we explored the role of LRRs in the function of PC1. Zebrafish expresses two human
PKD1
paralogs,
pkd1a
and
pkd1b
. Knockdown of both genes in zebrafish by morpholino antisense oligonucleotides produced phenotypes of dorsal-axis curvature and pronephric cyst formation. We found that overexpression of LRRs suppressed both phenotypes in
pkd1
-morphant zebrafish. Purified recombinant LRR domain inhibited proliferation of HEK cells in culture and interacted with the heterotrimeric basement membrane protein laminin-511 (α5β1γ1) in vitro. Mutations of amino acid residues in LRRs structurally predicted to bind laminin-511 disrupted LRR–laminin interaction in vitro and neutralized the ability of LRRs to inhibit cell proliferation and cystogenesis. Our data support the hypothesis that the extracellular region of PC1 plays a role in modulating PC1 interaction with the extracellular matrix and contributes to cystogenesis of PC1 deficiency.
Details
- Title: Subtitle
- Leucine-Rich Repeat in Polycystin-1 Suppresses Cystogenesis in a Zebrafish (Danio rerio) Model of Autosomal-Dominant Polycystic Kidney Disease
- Creators
- Biswajit Padhy - University of IowaMohammad Amir - University of IowaJian Xie - University of IowaChou-Long Huang - University of Iowa
- Resource Type
- Journal article
- Publication Details
- International journal of molecular sciences, Vol.25(5), 2886
- Publisher
- MDPI
- DOI
- 10.3390/ijms25052886
- PMID
- 38474131
- PMCID
- PMC10932423
- ISSN
- 1661-6596
- eISSN
- 1422-0067
- Grant note
- DK109887 / National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases
- Language
- English
- Date published
- 03/01/2024
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9984572458902771
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