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Updated: Aug 5, 2026
08:46
Implementing Patch Clamp and Live Fluorescence Microscopy to Monitor Functional Properties of Freshly Isolated PKD Epithelium
Published on: September 1, 2015
PKD1 upstream open reading frames affect Polycystin-1 expression and polycystic kidney disease phenotypes
Zhigui Li1, Zi Guo1, Soyoung Cho1
1Section of Nephrology, Yale School of Medicine, New Haven, United States of America.
The Journal of Clinical Investigation
|July 28, 2026
Summary
Inhibiting upstream open reading frames (uORFs) in PKD1 increases Polycystin-1 (PC1) protein levels. This approach prevents kidney cysts in models of autosomal dominant polycystic kidney disease (ADPKD), offering a new therapeutic strategy.
Area of Science:
- Genetics
- Molecular Biology
- Nephrology
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a leading cause of end-stage kidney failure.
- Reduced functional expression of PKD1/Polycystin-1 (PC1) underlies most ADPKD cases.
- Therapeutic strategies aim to restore adequate PC1 levels.
Purpose of the Study:
- To investigate the biological role of conserved PKD1 upstream open reading frames (uORFs).
- To determine if uORFs regulate Polycystin-1 (PC1) protein translation.
- To explore the therapeutic potential of modulating PKD1 uORFs.
Main Methods:
- Luciferase reporter assays were used to assess uORF activity.
- Humanized PKD1 5'UTR mouse models with uORF start codon edits were generated.
- Steric antisense oligonucleotides (ASOs) were employed to block uORF translation in vitro.
Main Results:
- Conserved PKD1 uORFs were identified and shown to initiate translation.
- Disabling uORFs (delta-uORF) increased PC1 protein expression 2-4 fold.
- uORF inhibition prevented kidney cyst formation in ADPKD models and increased PC1 in vitro.
Conclusions:
- PKD1 uORFs significantly contribute to low basal PC1 expression.
- Inhibiting PKD1 uORFs is a viable strategy to increase PC1 translation.
- Modulating uORFs presents a promising therapeutic avenue for ADPKD and related polycystic liver disease.
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