title: Aprt/Opn double knockout mice: osteopontin is a modifier of kidney stone disease severity.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Genetics, Rutgers University, Piscataway, New Jersey 08854-8082, USA.
authors.forename: Hilary J
authors.initials: HJ
authors.lastname: Vernon
authors.forename: Christine
authors.initials: C
authors.lastname: Osborne
authors.forename: Eleni G
authors.initials: EG
authors.lastname: Tzortzaki
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.forename: Jianmen
authors.initials: J
authors.lastname: Chen
authors.forename: Susan R
authors.initials: SR
authors.lastname: Rittling
authors.forename: David T
authors.initials: DT
authors.lastname: Denhardt
authors.forename: Steven
authors.initials: S
authors.lastname: Buyske
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Bledsoe
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Evan
authors.forename: Lynette
authors.initials: L
authors.lastname: Fairbanks
authors.forename: H Anne
authors.initials: HA
authors.lastname: Simmonds
authors.forename: Jay A
authors.initials: JA
authors.lastname: Tischfield
authors.forename: Amrik
authors.initials: A
authors.lastname: Sahota
mesh_terms: D000228:Adenine Phosphoribosyltransferase / Q000235:genetics*; D000818:Animals; D001835:Body Weight; D003094:Collagen / Q000378:metabolism; D003460:Crystallization; D005260:Female; D005355:Fibrosis; D006128:Growth; D017403:In Situ Hybridization; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007669:Kidney Calculi / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D008264:Macrophages / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D053495:Osteopontin; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D012720:Severity of Illness Index; D012727:Sex Characteristics; D012795:Sialoglycoproteins / Q000235:genetics*; D015996:Survival Rate; D014556:Urine / Q000737:chemistry; D014968:Xanthine Dehydrogenase / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin; D003094:Collagen; D014968:Xanthine Dehydrogenase; D000228:Adenine Phosphoribosyltransferase