Research article

Mutant polycystin-2 induces proliferation in primary rat tubular epithelial cells in a STAT-1/p21-independent fashion accompanied instead by alterations in expression of p57^KIP2 and Cdk2

Kyriacos N Felekkis^{* 1} , Panayiota Koupepidou^{* 1} , Evdokia Kastanos¹ , Ralph Witzgall² , Chang-Xi Bai³ , Li Li⁴ , Leonidas Tsiokas³ , Norbert Gretz⁴ and Constantinos Deltas¹

¹Department of Biological Sciences, University of Cyprus, Cyprus

²Institute for Molecular Anatomy, University of Regensburg, Germany

³Department of Cell Biology, University of Oklahoma Health Sciences Center, OK, USA

⁴Medical Research Center, University of Heidelberg, Mannheim, Germany

author email corresponding author email* Contributed equally

BMC Nephrology 2008, 9:10doi:10.1186/1471-2369-9-10

Published:	25 August 2008

Abstract

Background

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is characterized by the formation of multiple fluid-filled cysts that destroy the kidney architecture resulting in end-stage renal failure. Mutations in genes PKD1 and PKD2 account for nearly all cases of ADPKD. Increased cell proliferation is one of the key features of the disease. Several studies indicated that polycystin-1 regulates cellular proliferation through various signaling pathways, but little is known about the role played by polycystin-2, the product of PKD2. Recently, it was reported that as with polycystin-1, polycystin-2 can act as a negative regulator of cell growth by modulating the levels of the cyclin-dependent kinase inhibitor, p21 and the activity of the cyclin-dependent kinase 2, Cdk2.

Methods

Here we utilized different kidney cell-lines expressing wild-type and mutant PKD2 as well as primary tubular epithelial cells isolated from a PKD transgenic rat to further explore the contribution of the p21/Cdk2 pathway in ADPKD proliferation.

Results

Surprisingly, over-expression of wild-type PKD2 in renal cell lines failed to inactivate Cdk2 and consequently had no effect on cell proliferation. On the other hand, expression of mutated PKD2 augmented proliferation only in the primary tubular epithelial cells of a rat model but this was independent of the STAT-1/p21 pathway. On the contrary, multiple approaches revealed unequivocally that expression of the cyclin-dependent kinase inhibitor, p57^KIP2, is downregulated, while p21 remains unchanged. This p57 reduction is accompanied by an increase in Cdk2 levels.

Conclusion

Our results indicate the probable involvement of p57^KIP2 on epithelial cell proliferation in ADPKD implicating a new mechanism for mutant polycystin-2 induced proliferation. Most importantly, contrary to previous studies, abnormal proliferation in cells expressing mutant polycystin-2 appears to be independent of STAT-1/p21.