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Published on: September 1, 2015
Cyst growth, polycystins, and primary cilia in autosomal dominant polycystic kidney disease
1Department of Internal Medicine, Section of Nephrology, Yale University School of Medicine, New Haven, CT, USA.
Insights
Autosomal dominant polycystic kidney disease (ADPKD) may be slowed by disrupting cilia. Polycystin function normally represses a novel cilia-dependent pathway promoting cyst formation in ADPKD.
Area of Science:
- Nephrology
- Cell Biology
- Genetics
Background:
- The primary cilium in renal epithelia is crucial for sensing external signals.
- Polycystin (PC)1, encoded by the PKD1 gene, is central to autosomal dominant polycystic kidney disease (ADPKD).
- PC1 and PC2 proteins interact within primary cilia and are implicated in ADPKD pathogenesis.
Purpose of the Study:
- To investigate the role of polycystins and primary cilia in ADPKD.
- To explore a potential novel cilia-dependent pathway in cystogenesis.
- To understand how PC1 dosage affects ADPKD progression.
Main Methods:
- Analysis of polycystin (PC)1 and PC2 expression and function in renal epithelia.
- Investigating the impact of cilia structure and function on ADPKD development.
- Evaluating the effect of altered PC1 levels on cyst formation.
Main Results:
- Mutations in PKD1 or disrupted PC1/PC2 balance lead to ADPKD by affecting renal tubule architecture.
- Reduced PC1 levels or imbalance in PC1/PC2 can cause ADPKD features even without complete inactivation.
- Disrupting structurally intact cilia can significantly slow ADPKD progression caused by polycystin inactivation.
Conclusions:
- A novel cilia-dependent pathway, normally repressed by polycystin function, appears to promote cyst formation in ADPKD.
- These findings challenge current models and suggest a new understanding of ADPKD genetics and cilia signaling.
- Targeting cilia or this pathway could offer new therapeutic strategies for ADPKD.
Abstract:
The primary cilium of renal epithelia acts as a transducer of extracellular stimuli. Polycystin (PC)1 is the protein encoded by the PKD1 gene that is responsible for the most common and severe form of autosomal dominant polycystic kidney disease (ADPKD). PC1 forms a complex with PC2 via their respective carboxy-terminal tails. Both proteins are expressed in the primary cilia. Mutations in either gene affect the normal architecture of renal tubules, giving rise to ADPKD. PC1 has been proposed as a receptor that modulates calcium signals via the PC2 channel protein. The effect of PC1 dosage has been described as the rate-limiting modulator of cystic disease. Reduced levels of PC1 or disruption of the balance in PC1/PC2 level can lead to the clinical features of ADPKD, without complete inactivation. Recent data show that ADPKD resulting from inactivation of polycystins can be markedly slowed if structurally intact cilia are also disrupted at the same time. Despite the fact that no single model or mechanism from these has been able to describe exclusively the pathogenesis of cystic kidney disease, these findings suggest the existence of a novel cilia-dependent, cyst-promoting pathway that is normally repressed by polycystin function. The results enable us to rethink our current understanding of genetics and cilia signaling pathways of ADPKD.
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