The Protective Effects Of The Pioglitazone On The Autoimmune Injuries On Retinopathy In The STZ-induced Diabetics Rats

Aims:Diabetic retinopathy(DR) is one of the commonest chronic complication of the diabetes mellitus, which often complicated with hemorrhage and retinal detachment, resulting in decreased visual acuity or even blindness. DR is the microvascular disease and its pathogenesis is still not very clear. At present,the majority of studies revealed that insulin resistance (IR) of the fat cells is the main cause of the DM and its chronic complications. Recent studies, however, have revealed that autoimmune and inflammatory mechanisms were involved in the pathogenesis of IR on the muscle cells and may also be one of the mechanisms in the IR. Our previous study also found that immunosuppressive agents, Cyclosporine A(CsA) has an immunodepressive effect on the multiple organs of the STZ-induced DM rats. Furthermore, IR might be reduced by the same mechanisms. Pioglitazone (Piog) is one of the thiazolidinediones (TZDs) which is traditionarily believed to be an insulin sensitizer to enhance the combination between insulin and its receptor through the PPAR-y mechanisms. But Piog may also play an important modulatory effects on the autoimmune and inflammatory process. The aim of the pressent study is to study the protective effects of the Piog at various dosage on both retina and ocular muscles of the STZ-induced diabetic rats. Meanwhile, a comparison was made between CsA and Piog on their preventive effects for the pathogenesis and development of DR. In addition, our study also focused if Piog may affect the inflammatory response by reducing the expression of the insulin-like growth factor 1(IGF-1) and Interlukin 1β(IL-1β).Materials and methods:Ninety-six healthy male SD rats were randomly divided into DM group and healthy control group (CON). When the diabetic rat model was set up by intravenous administration of STZ, they were randomly divided into 6 groups,such as:low dose Piog group (PiogL), low dose Piog plus INS group (PiogL+I), large dose Piog group (PiogH), CsA group (CsA), CsA plus INS group (CsA+I), INS group (INS), and the group with no treatment(DM) respectively. Sixteen weeks later, all rats were sacrificed. Before that, the serum was derived and 24h urine was collected to evaluate the hepatic function, renal function, triglyceride and the urine albumin. Hematoxylin and Eosin Stain was used to observe the microstructure changes of the retinopathy and ocular muscles of the rats in each group. MASSON Stain was used to observe the fibrosis change. Retinopathy stretched preparation by trypsin was used to observe the vasculopathy. Furthermore, the deposition of immunoglobulins was detected by immunohistochemistry and immunofluorescence. At last, the expression of IL-1βand IGF-1 mRNA and protein were examined by RT-PCR and immunohistochemistry, respectively.Result:The rats in DM group had typical retinopathy and pathological changes in the ocular muscles. The deposition of the Ig on the retina and ocular muscles was significantly increased, especially IgG, so did the expression of IL-1βand IGF-1 mRNA and protein. The change in microstructure of retina and ocular muscles in PiogH group were close to CON group, CsA and CsA+I group, which were better than PiogL and PiogL+I group. In each Piog interfering group, the deposition of the Ig in the retina and ocular muscles was apparently decreased, especially in PiogH group, which were close to CsA and CsA+I group. The expression of the mRNA and protein of IL-1βand IGF-1 in the retina and ocular muscles in Piog groups was apparently, reduced especially in PiogH group which was less than which in PiogL and Piog+I group while were close to CsA and CsA+I group.Conclusion:There were autoimmune injuries in retina and ocular muscles in the STZ-induced DM rats. The similar effect was found in the group treaated with large dose of Piog similar to the group treated with CsA, which had been confirmed to have an obvious protective effects on the retina and ocular muscles in the diabetic rats. The possible mechanisms of these immunoprotective effects might be due to the reduction in the deposition of immunoglobulins on the related organs and tissues, which was followed by the reduction in the expression and activity of the inflammatory factor, such as IL-1βand IGF-1. So inflammatory responses in these tissues were alleviated and the structure and function were preserved. For the above reasons, Piog can be used not only as INS sensitizer but also as an immunomodulator for preventing the tissue from autoimmune damage on multiple organs of DM.