Reduced tolerance to acute renal ischemia in mice with a targeted disruption of the osteopontin gene.
BACKGROUND
Mice with a targeted disruption of the osteopontin gene through homologous recombination in embryonic stem cells have recently been generated and shown to be characterized by unaltered fertility and normal embryonic and postnatal development, including renal development, but altered osteoclastogenesis from spleen progenitors. The lack of detectable pathological manifestations in kidneys of mice with the targeted disruption of the osteopontin gene (opn -/-) makes them an excellent model for studies of pathophysiological processes that are thought to be accompanied by changes in renal osteopontin expression. It has previously been suggested that osteopontin may play an important role in the pathophysiology of acute renal failure, thus prompting this study.


METHODS
Wild-type and opn -/- mice were subjected to 30 minutes of renal ischemia and were studied 24 hours later.


RESULTS
Control opn +/+ mice showed a significant retention of blood urea nitrogen and creatinine, which is indicative of the development of ischemic acute renal dysfunction. This was accompanied by a 2.7-fold increase in the immunodetectable osteopontin compared with sham-operated control. Animals with the disrupted osteopontin gene exhibited ischemia-induced renal dysfunction, which was twice as pronounced as that observed in mice with the intact osteopontin response to stress. In addition, the structural damage to the ischemic kidneys obtained from opn -/- mice was more pronounced than that observed in similarly treated wild-type mice. This was associated with the augmented expression of inducible nitric oxide synthase and the prevalence of nitrotyrosine residues in kidneys from opn -/- mice versus wild-type counterparts. In vitro studies with proximal tubular cells subjected to hypoxia in the presence of OPN, but not OPN with deleted arginine-glycine-aspartic acid (RGD) domain, resulted in cytoprotection.


CONCLUSIONS
The comparative analysis of functional and morphological sequelae of acute renal ischemia in opn +/+ and opn -/- mice provides strong evidence of renoprotective action of osteopontin in acute ischemia.
Noiri
E
E
Department of Medicine, The University of Tokyo, Japan.
Dickman
K
K
Miller
F
F
Romanov
G
G
Romanov
V I
VI
Shaw
R
R
Chambers
A F
AF
Rittling
S R
SR
Denhardt
D T
DT
Goligorsky
M S
MS
D000208:Acute Disease; D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D018390:Gene Targeting; D000860:Hypoxia / Q000378:metabolism; D007511:Ischemia / Q000235:genetics* / Q000503:physiopathology*; D007687:Kidney Tubules, Proximal / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D053495:Osteopontin; D012079:Renal Circulation / Q000502:physiology*; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin