MMP/ TIMP balance is modulated in vitro by 15dPGJ(2) in fetuses and placentas from diabetic rats.
BACKGROUND
Maternal diabetes is associated with morphological placental abnormalities and foeto-placental impairments. These alterations are linked with a dysregulation of the activity of matrix metalloproteinases (MMPs). We investigated the action of 15deoxyDelta(12,14) prostaglandin J(2) (15dPGJ(2)), a natural ligand of the peroxisome proliferator activated receptor (PPAR) gamma, on MMP-2 and MMP-9 activities and tissue inhibitors of matrix metalloproteinases (TIMP) levels in foetuses and placentas from diabetic rats.


METHODS
Diabetes was induced in rat neonates by a single streptozotocin administration (90 mg kg(-1) s.c.). At 13.5 days of gestation, foetal and placental homogenates were prepared for the determination of PPARgamma levels (western blot) and 15dPGJ(2) concentration (enzyme-immunoassay), whereas the in vitro effect of 15dPGJ(2) (2 microM) was evaluated on placental and foetal MMPs and TIMP activities (zymography and reverse zymography), nitrate/nitrite concentrations (Griess method) and thiobarbituric acid reactive substances (TBARS).


RESULTS
PPARgamma was increased while 15dPGJ(2) was decreased in placentas and foetuses from diabetic rats. 15dPGJ(2) additions were able to reduce the high activities of MMP-2 and MMP-9 present in diabetic placental tissues. 15dPGJ(2) additions reduced MMP-2 activity in control and diabetic foetuses. TIMP-3 levels were decreased in diabetic placentas and 15dPGJ(2) was able to enhance them to control values. Nitrates/nitrites and TBARS, metabolites of MMPs activators, were increased in the diabetic placenta and reduced by 15dPGJ(2).


CONCLUSIONS
This study demonstrates that 15dPGJ(2) is a potent modulator of the balance between MMP activities and TIMP levels, which is needed in the correct formation and function of the placenta and foetal organs.
Pustovrh
M C
MC
Laboratory of Reproduction and Metabolism, Center for Pharmacological and Botanical Studies, CEFyBO-CONICET, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina.
Capobianco
E
E
Martínez
N
N
Higa
R
R
White
V
V
Jawerbaum
A
A
D000818:Animals; D003920:Diabetes Mellitus / Q000201:enzymology / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005333:Fetus / Q000187:drug effects* / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D019714:Tissue Inhibitor of Metalloproteinases / Q000187:drug effects / Q000378:metabolism
C477819:15-deoxyprostaglandin J2; D047495:PPAR gamma; D019714:Tissue Inhibitor of Metalloproteinases; D009569:Nitric Oxide; D018093:Gelatinases; D020782:Matrix Metalloproteinases; D015230:Prostaglandin D2