Estrogen replacement therapy in diabetic ovariectomized female rats potentiates postischemic leukocyte adhesion in cerebral venules via a RAGE-related process.
In this study, we tested the hypothesis that the documented transformation of 17beta-estradiol (E2) from a counterinflammatory hormone in nondiabetic (ND) rats to a proinflammatory agent in rats with diabetes mellitus (DM) is due to an enhanced contribution from the receptor for advanced glycation end products (RAGE). Rhodamine 6G-labeled leukocytes were observed through a closed cranial window in rats. In vivo pial venular leukocyte adherence and infiltration were measured over 10 h reperfusion after transient forebrain ischemia in DM (streptozotocin) versus ND intact, ovariectomized (OVX), and E2-replaced (for 7-10 days) OVX (OVE) females. The role of RAGE was examined in two ways: 1) RAGE knockdown via topical application of RAGE antisense versus missense oligodeoxynucleotide or 2) intracerebroventricular injection of the RAGE decoy inhibitor, soluble RAGE. Among diabetic rats, the lowest levels of cortical RAGE mRNA and immunoreactivity of the RAGE ligand, AGE, were seen in OVX females, with significantly higher levels exhibited in intact and OVE females. However, results from the analysis of cortical RAGE protein only partially tracked those findings. When comparing ND to DM rats, cortical AGE immunoreactivity was significantly lower in OVE and intact females but similar in OVX rats. In DM rats, the level of postischemic leukocyte adhesion and infiltration (highest to lowest) was OVE>intact>>untreated OVX. In NDs, adhesion was highest in the untreated OVX group. Leukocyte extravasation was observed at >6 h postischemia but only in diabetic OVE and intact females and in ND OVX (untreated) rats. Pretreatment with RAGE antisense-oligodeoxynucleotide or soluble RAGE attenuated postischemic leukocyte adhesion and prevented infiltration but only in the diabetic OVE and intact groups. These results indicate that the exacerbation of postischemic leukocyte adhesion by chronic E2 replacement therapy in diabetic OVX females involves a RAGE-related mechanism. Targeting RAGE may restore the neuroprotective effect of E2 replacement therapy in diabetic females.
Xu
Hao-Liang
HL
Neuroanesthesia Research Laboratory, Department of Anesthesiology, University of Illinois at Chicago, 835 S. Wolcott Ave., Rm. E-714C, Chicago, IL 60612, USA.
Vetri
Francesco
F
Lee
Hae-Kyung
HK
Ye
Shuhua
S
Paisansathan
Chanannait
C
Mao
Lizhen
L
Tan
Fulong
F
Pelligrino
Dale A
DA
D000818:Animals; D002545:Brain Ischemia / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D002448:Cell Adhesion / Q000187:drug effects*; D002540:Cerebral Cortex / Q000098:blood supply / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002560:Cerebrovascular Circulation; D003921:Diabetes Mellitus, Experimental / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D004958:Estradiol / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D015914:Estrogen Replacement Therapy / Q000009:adverse effects*; D005260:Female; D055785:Gene Knockdown Techniques; D017127:Glycation End Products, Advanced / Q000378:metabolism; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D017078:Laser-Doppler Flowmetry; D007962:Leukocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D010052:Ovariectomy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000008:administration & dosage / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014699:Venules / Q000187:drug effects / Q000276:immunology
D017127:Glycation End Products, Advanced; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D004958:Estradiol