Effect Of Losartan On Retinal Leukostasis In The Diabetic Rat

Background:With the development of human life,the number of diabetic patients increases.Diabetic retinopathy,the serious complication of diabetic has become the first cause of growing blind between the age of 20-74 in developed countries.It is characterized by reduction of perithelial cell,basal membrane thickening,capillary lumen diminished,capillary endothelium barrier decompensation;its clinical manifestation includes microaneurysm,ecchymosis, hard- ness effusion,cotton flock,venobead-like,retina microcircula- tion abnormality and macular edema et al.The pathogenesis of diabetic retinopathy is rather complicated.Hyperglycaemia, polyalcohol- cyclohexanhexol metabolism abnormality, hemodyna- mics disorder,clotting mechanism dysfunction,proteinaceous nonenzy- matic glycosylation,oxyradical formation,cytokine, adhe- sion molecule, retina nerves,inflammation,candidate gene, immune factor and so on.Multitude factors working together contribute to the genesis of diabetic retino- pathy.In the early stage of diabetic retinopathy,leucocytes stick to endothelial cell,once this happened may result in retina endodermis functional disturbance,retina perfuse abnormality,blood vessel permeability and blood-retina barrier alteration, thereby leading to diabetic retina blood capillary obstruction,microthrombus and neovascularization.The process is mediated by adhesion molecule.ICAM-1 is one of the most important adhesion molecule attributing to diabetic retinopathy.Adhesion molecules express on the surface of cell.They are the glucoprotein that mediate intra- or extracellular matrix to interact. They combine with matching acceptor,to form lattice,mediating cell-cell junction,and transfer signal, participating to regular the function of cell accrementition. At present,we have already known adhesion molecule belonging to five superfamily.They are immune globulin superfamily,integrin family,selectin superfamily,calcium rely adhesion molecule superfamily and H2 cell adhesion molecule superfamily.ICAM-1 belongs to immune globulin superfamily.It can express on the surface of leucocyte,fibroblast,endothelial cell and endotheliocyte.It is the important molecule that mediate leukokinesis and adherent.With the recognition of the disease,many kinds of drugs and praeparatum have been used to prevent the occurrence and development of diabetic retinopathy.Among the total,blood vessel growth regulation factor,inflammatory reaction inhibitor,advanced glycosylation end product inhibitor,antioxidant,adsorb oxygen, aldose reductase inhibitors,traditional Chinese medicine drug et al have been confirmed effectively to diabetic retinopathy.Losartan is the latest generation of hypotensive drug.It belongs to angiotensinâ…¡receptor antagonist.Losartan has the function of depressing the blood pressure,resisting the congestive heart failure,kidney protection and brain protection.At prsent,the researches of the relationship between RAS system and diabetic retinopathy suggest that:the components of the RAS are present in the eye, and intraocular and serum levels of angiotensinII,renin,and angiotensin-convert in genzyme(ACE) correlate significantly with the severity of retinopathy. Angiotensin II inhibitors arrest or delay progressive breakdown of the blood- retina barrier in normotensive insulin-dependent diabetic patients with nephropathy and have favorable effects on normotensive patients with insulin-dependent diabetic retinopathy. Angiotensin II inhibitors also have the depressant effect on VEGF and other factors.But is there relationship between RAS system and leukostasis? Angiotensin II inhibitors as the drug to decrease the formation of Angiotensin II,its relationship between leukostasis has not been reported in our country.We use the diabetic rats breeded for 2 weeks,breaking the mode of diabetic rats model breeded for 1month,3month,6month or even more time. The theory based on Tang shi-bo et al's finding that after diabetic model successfully induced 3days,the expression of CD45 was significantly increased in the retinal capillary, and reached a peak at the 14th day,the retinal vascular leukocytosis, accumulating just like bead,aferward stabilize in this level.Hughes et al examined the rat for retinal leukostasis in vivo with a scanning laser ophthalmoscope(SLO).The same trend was observed when leukostasis was analyzed on retinal flat mounts with concanavalin A and CD45 immunofluorescence.Assays of gene expression of retinal intercellular adhesion molecule (ICAM-1) by semi-quantita- tive RT-PCR.They all indicate that losartan has the effect on leukostasis of the rats that breeded and treated for 2 weeks.We use the method of immunohistochemical different from Hughes et al using,to know the leukostasis by observing the ICAM-1.Objective:To study if the endogenous renin-angiotensin system affects diabetic retinal leukostasis.Methods:Rats with streptozotocin-induced diabetes were treated with an angiotensinâ…¡AT1 receptor antagonist(losartan).The rats were divided into 3 groups:(1)normal control group(n=10),(2)Diabetic group without therapy(n=10),(3)losartan group(n=10).After 2 weeks,the rats were examined for the expression of ICAM-1 by immunohistochemistry method.Results:There was no ICAM-1 expressed in the retino of normal diabebic rats.In diabetic group,the expression of ICAM-1 increased. Losartan group also have the expression of ICAM-1 but less than the diabetic group,similarly to normal group. Conclusion:Losartan can depressed the expression of ICAM-1 in diabetic retino,it may suppresses the development of diabetic retinopathy.