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, Amrik Sahota

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)938-947
Number of pages10
JournalKidney international
Volume68
Issue number3
DOIs
StatePublished - Sep 1 2005
Externally publishedYes

Keywords

  • 2,8-dihydroxyadenine
  • Adenine phosphoribosyltransferase
  • Inflammation
  • Kidney stone disease
  • Osteopontin
  • Xanthine dehydrogenase

ASJC Scopus subject areas

  • Nephrology

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  • Cite this

    Vernon, H. J., Osborne, C., Tzortzaki, E. G., Yang, M., Chen, J., Rittling, S. R., Denhardt, D. T., Buyske, S., Bledsoe, S. B., Evan, A. P., Fairbanks, L., Simmonds, H. A., Tischfield, J. A., & Sahota, A. (2005). Aprt/Opn double knockout mice: Osteopontin is a modifier of kidney stone disease severity. Kidney international, 68(3), 938-947. https://doi.org/10.1111/j.1523-1755.2005.00487.x