Acceleration of polycystic kidney disease progression in cpk mice carrying a deletion in the homeodomain protein Cuxl

摘要

Acceleration of polycystic kidney disease progression in cpk mice carrying a deletion in the homeodomain protein Cuxl. Am J Physiol Renal Physiol 295: F1725-F1734, 2008. First published October 1, 2008; doi: 10.1152/ajprenal.90420.2008.-Polycystic kidney diseases (PKD) are inherited as autosomal dominant (ADPKD) or autosomal recessive (ARPKD) traits and are characterized by progressive enlargement of renal cysts. Aberrant cell proliferation is a key feature in the progression of PKD. Cuxl is a homeobox gene that is related to Drosophila cut and is the murine homolog of human CDP (CCAAT Displacement Protein). Cuxl represses the cyclin kinase inhibitors p21 and p27, and transgenic mice ectopically expressing Cuxl develop renal hyperplasia. However, Cuxl transgenic mice do not develop PKD. Here, we show that a 246 amino acid deletion in Cuxl accelerates PKD progression in cpk mice. Cystic kidneys isolated from 10-day-old cpk/Cuxl double mutant mice were significantly larger than kidneys from 10-day-old cpk mice. Moreover, renal function was significantly reduced in the Cuxl mutant cpk mice, compared with cpk mice. The mutant Cuxl protein was ectopically expressed in cyst-lining cells, where expression corresponded to increased cell proliferation and apoptosis, and a decrease in expression of the cyclin kinase inhibitors p27 and p21. While the mutant Cuxl protein altered PKD progression, kidneys from mice carrying the mutant Cuxl protein alone were phenotypically normal, suggesting the Cuxl mutation modifies PKD progression in cpk mice. During cell cycle progression, Cuxl is proteolytically processed by a nuclear isoform of the cysteine protease cathepsin-L. Analysis of the deleted sequences reveals that a cathepsin-L processing site in Cuxl is deleted. Moreover, nuclear cathepsin-L is significantly reduced in both human ADPKD cells and in Pkdl null kidneys, corresponding to increased levels of Cuxl protein in the cystic cells and kidneys. These results suggest a mechanism in which reduced Cuxl processing by cathepsin-L results in the accumulation of Cuxl, downregulation of p21/p27, and increased cell proliferation in PKD