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Mutant Tamm-Horsfall Glycoprotein Accumulation in Endoplasmic Reticulum Induces Apoptosis Reversed by Colchicine and Sodium 4-Phenylbutyrate

Sung Won Choi^*, Ok Hee Ryu^*, Sun Jin Choi^*, In Sun Song^*, Anthony J. Bleyer and Thomas C. Hart^*

^* Human Craniofacial Genetics Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland; and Section on Nephrology, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Address correspondence to: Dr. Thomas C. Hart, NIH-NIDCR, 10 Center Drive, Building 10, Room 5-2531, Bethesda, MD 20892-1432. Phone: 301-402-1706; Fax: 301-480-4455; E-mail: thart{at}mail.nih.gov

Received for publication May 4, 2005. Accepted for publication July 18, 2005.

As a consequence of uromodulin gene mutations, individuals develop precocious hyperuricemia, gout, and progressive renal failure. In vitro studies suggest that pathologic accumulation of uromodulin/Tamm-Horsfall glycoprotein (THP) occurs in the endoplasmic reticulum (ER), but the pathophysiology of renal damage is unclear. It was hypothesized that programmed cell death triggered by accumulation of misfolded THP in the ER causes progressive renal disease. Stably transfected human embryonic kidney 293 cells and immortalized thick ascending limb of Henle’s loop cells with wild-type and mutated uromodulin cDNA were evaluated to test this hypothesis. Immunocytochemistry, ELISA, and deglycosylation studies indicated that accumulation of mutant THP occurred in the ER. FACS analyses showed a significant increase in early apoptosis signal in human embryonic kidney 293 and thick ascending limb of Henle’s loop cells that were transfected with mutant uromodulin constructs. Colchicine and sodium 4-phenylbutyrate treatment increased secretion of THP from the ER to the cell membrane and into the culture media and significantly improved cell viability. These findings indicate that intracellular accumulation of THP facilitates apoptosis and that this may provide the pathologic mechanism responsible for the progressive renal damage associated with uromodulin gene mutations. Colchicine and sodium 4-phenylbutyrate reverse these processes and could potentially be beneficial in ameliorating the progressive renal damage in uromodulin-associated kidney diseases.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673