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Implementing Patch Clamp and Live Fluorescence Microscopy to Monitor Functional Properties of Freshly Isolated PKD Epithelium
Published on: September 1, 2015
Altered Hippo signalling in polycystic kidney disease
Hester Happé1, Annemieke M van der Wal, Wouter N Leonhard
1Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
The Journal of Pathology
|March 8, 2011
Summary
Autosomal dominant polycystic kidney disease (ADPKD) involves kidney cyst formation. In ADPKD kidneys, the Hippo-signalling pathway component YAP accumulates in the nucleus, promoting cyst growth and upregulating targets like Four-jointed (Fjx1).
Area of Science:
- Nephrology
- Molecular Biology
- Cell Biology
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a leading cause of end-stage renal disease, characterized by kidney cyst formation and progressive renal function decline.
- Previous studies indicated tubular epithelial injury accelerates cystogenesis in Pkd1-deletion mouse models.
- The planar cell polarity (PCP) component Four-jointed (Fjx1) exhibits altered expression during epithelial repair and in cystic kidneys, suggesting a role in ADPKD pathogenesis.
Purpose of the Study:
- To investigate the activity of the Hippo-signalling pathway in ADPKD.
- To determine the role of the Hippo pathway effector Yes-associated protein (YAP) during epithelial repair and cyst formation in ADPKD.
- To explore the relationship between Fjx1, PCP, and Hippo signalling in the context of ADPKD.
Main Methods:
- Analysis of YAP expression and localization in inducible Pkd1-deletion mice during epithelial repair and cystogenesis.
- Examination of YAP transcriptional targets, including Fjx1, in cystic kidney epithelia.
- Assessment of Hippo pathway activity in renal tissues from human ADPKD and autosomal recessive polycystic kidney disease (ARPKD) patients and cystic renal tumors.
Main Results:
- During tissue repair in Pkd1-deletion mice, YAP expression normalized after an initial increase.
- In cystic epithelia and dilated tubules, strong nuclear YAP accumulation was observed, alongside upregulation of YAP targets Birc-3, Ctgf, InhbA, and Fjx1.
- Altered Hippo pathway activity, indicated by YAP nuclear localization, was confirmed in human ADPKD/ARPKD tissues and cystic renal tumors.
Conclusions:
- Four-jointed (Fjx1) is involved in PCP signalling during epithelial repair but is linked to Hippo signalling and cyst growth in cystic kidneys.
- The Hippo-signalling pathway, particularly nuclear YAP accumulation, plays a significant role in ADPKD cystogenesis.
- These findings highlight the Hippo pathway as a potential therapeutic target for ADPKD.
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