Polycystic kidney disease (PKD) is the most common heritable disease in humans. Patients with autosomal dominant polycystic kidney disease (ADPKD) have epithelial cysts in the kidney, liver and pancreas, and often suffer from abdominal hernias, intracranial aneurysms, gastrointestinal cysts and cardiac valvular defects. These conditions are often associated with altered extracellular matrix (ECM) production. Despite a decade of work on the principal ADPKD genes, PKD1 and PKD2, questions remain about the etiology of cystic disease and the role of the ECM in ADPKD pathology.

The authors created a zebrafish model with deficiencies in polycystin1 and polycystin2, similar to those found in humans with ADPKD. The zebrafish is a convenient model, since multiple genes can be inhibited simultaneously using antisense morpholino oligonucleotides to produce a large number of rapidly developing embryos in which tissue pathology can be studied. This study exploits a robust and easily scored axis curvature defect in polycystin-deficient zebrafish embryos to define the role of polycystins in ECM production.

Both polycystin1- and polycystin2-deficient embryos exhibit dorsal curved body axis defects that correlate with excess production of type II collagen around the notochord, the main structural element of the embryonic zebrafish trunk. Collagen genes, like many genes that encode embryonic structural proteins, are initially expressed at a high level and then shut off after tissue formation. Excess collagen in polycystin-deficient embryos correlates with abnormally persistent expression of multiple notochord collagen genes, suggesting that, in the absence of polycystins, embryonic genes do not shut off properly. Distortion of the body axis in polycystin-deficient zebrafish embryos was relieved by concomitant inhibition of collagen production. Other treatments that prevented collagen crosslinking also relieved the body axis distortion. This suggests that polycystins provide a feedback sensor of tissue formation, signaling the completion of morphogenesis and suppressing further matrix deposition.

This work points to a broader role for polycystins in tissue formation than was previously appreciated, and makes direct links between polycystin signaling and matrix gene expression. There is therapeutic potential to restoring polycystin-mediating signaling (which is common in healthy organs) in diseased polycystin-deficient cells. This will require greater understanding of the mechanisms that polycystins use to regulate ECM production. Some signaling pathways involving intracellular calcium release and phosphoinositide 3-kinase (PI3K) may be involved since disruption of these systems is shown to induce similar overexpression of collagen genes in the zebrafish notochord.

This work also establishes a zebrafish model for human ADPKD. It defines the molecular end points of ADPKD tissue pathology in zebrafish, and suggests that it is feasible to perform large-scale screening of drugs and small molecules for those that could revert the disease phenotype.

2010