Loss of Polycystin-1 in Human Cyst-Lining Epithelia Leads to Ciliary Dysfunction
| Autor: | Robert J. Kolb, Mark B. Consugar, Francis J. Alenghat, Jing Zhou, Surya M. Nauli, Mahmoud Loghman-Adham, Donald E. Ingber, Peter C. Harris, Sandro Rossetti |
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| Rok vydání: | 2006 |
| Předmět: |
Nephrology
medicine.medical_specialty Pathology TRPP Cation Channels Autosomal dominant polycystic kidney disease Biology urologic and male genital diseases Mechanotransduction Cellular Models Biological Epithelium Calcium in biology Mice Internal medicine medicine Animals Humans Cyst Cilia Calcium metabolism Base Sequence Mechanosensation PKD1 urogenital system DNA General Medicine Polycystic Kidney Autosomal Dominant medicine.disease female genital diseases and pregnancy complications Cell biology Mutation Calcium Kidney disease |
| Zdroj: | Journal of the American Society of Nephrology. 17:1015-1025 |
| ISSN: | 1046-6673 |
| DOI: | 10.1681/asn.2005080830 |
| Popis: | A "two-hit" hypothesis predicts a second somatic hit, in addition to the germline mutation, as a prerequisite to cystogenesis and has been proposed to explain the focal nature for renal cyst formation in autosomal dominant polycystic kidney disease (ADPKD). It was reported previously that Pkd1(null/null) mouse kidney epithelial cells are unresponsive to flow stimulation. This report shows that Pkd1(+/null) cells are capable of responding to mechanical flow stimulation by changing their intracellular calcium concentration in a manner similar to that of wild-type cells. This paper reports that human renal epithelia require a higher level of shear stress to evoke a cytosolic calcium increase than do mouse renal epithelia. Both immortalized and primary cultured renal epithelial cells that originate from normal and nondilated ADPKD human kidney tubules display normal ciliary expression of the polycystins and respond to fluid-flow shear stress with the typical change in cytosolic calcium. In contrast, immortalized and primary cultured cyst-lining epithelial cells from ADPKD patients with mutations in PKD1 or with abnormal ciliary expression of polycystin-1 or -2 were not responsive to fluid shear stress. These data support a two-hit hypothesis as a mechanism of cystogenesis. This report proposes that calcium response to fluid-flow shear stress can be used as a readout of polycystin function and that loss of mechanosensation in the renal tubular epithelia is a feature of PKD cysts. |
| Databáze: | OpenAIRE |
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