Loss of polycystin-1 in human cyst-lining epithelia leads to ciliary dysfunction

Surya M. Nauli, Sandro Rossetti, Robert J. Kolb, Francis J. Alenghat, Mark B. Consugar, Peter C. Harris, Donald E. Ingber, Mahmoud Loghman-Adham, Jing Zhou

Research output: Contribution to journalArticle

130 Scopus citations

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 Pkd1null/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.

Original languageEnglish (US)
Pages (from-to)1015-1025
Number of pages11
JournalJournal of the American Society of Nephrology
Volume17
Issue number4
DOIs
StatePublished - Apr 1 2006

ASJC Scopus subject areas

  • Nephrology

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    Nauli, S. M., Rossetti, S., Kolb, R. J., Alenghat, F. J., Consugar, M. B., Harris, P. C., Ingber, D. E., Loghman-Adham, M., & Zhou, J. (2006). Loss of polycystin-1 in human cyst-lining epithelia leads to ciliary dysfunction. Journal of the American Society of Nephrology, 17(4), 1015-1025. https://doi.org/10.1681/ASN.2005080830