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.


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.
Vernon
Hilary J
HJ
Department of Genetics, Rutgers University, Piscataway, New Jersey 08854-8082, USA.
Osborne
Christine
C
Tzortzaki
Eleni G
EG
Yang
Min
M
Chen
Jianmen
J
Rittling
Susan R
SR
Denhardt
David T
DT
Buyske
Steven
S
Bledsoe
Sharon B
SB
Evan
Andrew P
AP
Fairbanks
Lynette
L
Simmonds
H Anne
HA
Tischfield
Jay A
JA
Sahota
Amrik
A
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
D012333:RNA, Messenger; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin; D003094:Collagen; D014968:Xanthine Dehydrogenase; D000228:Adenine Phosphoribosyltransferase