Genetic Disorders – Development
Kidney International (2005) 68, 938–947; doi:10.1111/j.1523-1755.2005.00487.x
Aprt/Opn double knockout mice: Osteopontin is a modifier of kidney stone disease severity
HILARY J VERNON, CHRISTINE OSBORNE, ELENI G TZORTZAKI, MIN YANG, JIANMEN CHEN, SUSAN R RITTLING, DAVID T DENHARDT, STEVEN BUYSKE, SHARON B BLEDSOE, ANDREW P EVAN, LYNETTE FAIRBANKS, H ANNE SIMMONDS, JAY A TISCHFIELD and AMRIK SAHOTA
Department of Genetics, Rutgers University, Piscataway, New Jersey; Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey; Department of Statistics, Rutgers University, Piscataway, New Jersey; Faculty of Medicine, University of Crete, Crete, Greece; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana; and Purine Research Laboratory, Guy's Hospital, London, United Kingdom
Correspondence: Amrik Sahota, Ph.D., Department of Genetics, Nelson Laboratories, Rutgers University, 604 Allison Road, Piscataway, NJ 08854–8082. E-mail: sahota@biology.rutgers.edu
Received 19 September 2004; Revised 27 December 2004; Re-revised 7 March 2005; Accepted 30 March 2005.
Abstract
Aprt/Opn double knockout mice: Osteopontin is a modifier of kidney stone disease severity.
Background
Osteopontin (OPN) is reported to have two distinct functions in kidney disease: Promotion of inflammation at sites of tissue injury, and inhibition of calcium oxalate monohydrate stone formation. However, many of the studies supporting these functions were carried out in animal models of acute renal injury or in cultured cells; thus, the role of OPN in chronic renal disease is not well defined. We examined the role of OPN in adenine phosphoribosyltransferase (Aprt) knockout mice, in which inflammation and formation of 2,8-dihydroxyadenine (DHA) kidney stones are prominent features, by generating Aprt/Opn double knockout mice.
Methods
We characterized the phenotypes of six- and 12-week-old Aprt-/- Opn-/-, Aprt-/- Opn+/+, Aprt+/+ Opn-/-, and Aprt+/+ Opn+/+ male and female mice using biochemical, histologic, immunohistochemical, and in situ hybridization techniques.
Results
At 6 weeks of age, there was no difference in phenotype between double knockout and Aprt knockout mice. At 12 weeks, there was increased adenine and DHA excretion, renal crystal deposition, and inflammation in double knockout versus Aprt knockout male mice. Double knockout and Aprt knockout female mice at 12 weeks had less pathology than their male counterparts, but kidneys from double knockout females showed more inflammation compared with Aprt knockout females; both genotypes had similar levels of DHA crystal deposition.
Conclusion
We conclude that (1) OPN is a major inhibitor of DHA crystal deposition and inflammation in male mice; and (2) OPN is a major modifier of the inflammatory response but not of crystal deposition in female mice. Thus, separate mechanisms appear responsible for the tissue changes seen in DKO males versus females.
Keywords:
adenine phosphoribosyltransferase, 2,8-dihydroxyadenine, inflammation, kidney stone disease, osteopontin, xanthine dehydrogenase
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