Effects of cyclosporine in osteopontin null mice.
BACKGROUND
Osteopontin (OPN) is a macrophage adhesive and cell survival factor that is up-regulated in tubules in tubulointerstitial disease. We have previously reported that rats with cyclosporine (CsA) nephropathy have increased tubular osteopontin that correlates with the infiltration of macrophages and interstitial fibrosis. This study tested the hypothesis that the absence of OPN would ameliorate CsA nephropathy.


METHODS
OPN knockout (-/-) and wild type (+/+) mice were fed a low salt diet (Na+ 0.01%) for one week and then received daily CsA injections (30 mg/kg, SC) until sacrifice at two weeks. Afferent arteriolopathy, tubulointerstitial injury, macrophage infiltration, collagen III deposition, transforming growth factor-beta (TGF-beta) expression, and tubular and interstitial cell proliferation and apoptosis were evaluated.


RESULTS
Wild type mice developed early features of CsA nephropathy, with arteriolar hyalinosis and cortical and tubulointerstitial fibrosis. Despite comparable CsA levels, OPN-/- mice had less arteriolopathy (15 vs. 24%, P < 0.05), a 20% reduction in cortical macrophage infiltration (P < 0.05), and 20% reduction in interstitial collagen deposition (P < 0.05). OPN-/- mice also showed less cortical interstitial cell proliferation but no differences in tubular cell proliferation or apoptosis. OPN+/+ mice also developed some neurotoxicity, consisting of ataxia, and this was associated with increased mortality at two weeks.


CONCLUSIONS
OPN partially mediates arteriolopathy, early macrophage recruitment and fibrosis in murine CsA nephropathy. OPN also may be involved in CsA associated neurotoxicity.
Mazzali
Marilda
M
Division of Nephrology, Department of Pathology, University of Washington, Seattle, Washington, USA.
Hughes
Jeremy
J
Dantas
Marcio
M
Liaw
Lucy
L
Steitz
Susan
S
Alpers
Charles E
CE
Pichler
Raimund H
RH
Lan
Hui Y
HY
Giachelli
Cecilia M
CM
Shankland
Stuart J
SJ
Couser
William G
WG
Johnson
Richard J
RJ
D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D016572:Cyclosporine / Q000633:toxicity*; D005355:Fibrosis; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D053495:Osteopontin; D012333:RNA, Messenger / Q000032:analysis; D012795:Sialoglycoproteins / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1
D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053495:Osteopontin; D016572:Cyclosporine