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Loss of polycystin-1 in human cyst-lining epithelia leads to ciliary dysfunction.
- Source :
-
Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2006 Apr; Vol. 17 (4), pp. 1015-25. - Publication Year :
- 2006
-
Abstract
- 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.
- Subjects :
- Animals
Base Sequence
Calcium metabolism
Cilia pathology
DNA genetics
Epithelium physiopathology
Humans
Mechanotransduction, Cellular genetics
Mechanotransduction, Cellular physiology
Mice
Models, Biological
Mutation
Polycystic Kidney, Autosomal Dominant etiology
Polycystic Kidney, Autosomal Dominant genetics
Polycystic Kidney, Autosomal Dominant pathology
Cilia physiology
Polycystic Kidney, Autosomal Dominant physiopathology
TRPP Cation Channels metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1046-6673
- Volume :
- 17
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of the American Society of Nephrology : JASN
- Publication Type :
- Academic Journal
- Accession number :
- 16565258
- Full Text :
- https://doi.org/10.1681/ASN.2005080830