Theoretical Study On The Effect Of JAK-STATt Signaling Pathway On Lipid Metabolism In Type 2 Diabetic Nephropathy Model

Objective: To determine the renal activation pattern of JAK-STAT signaling pathway in diabetic nephropathy(DN)mouse and rat models,and explore the effects of JAK-STAT pathway activation on the renal function,pathology and lipid metabolism of diabetic mice/rats.Gaining insights,with respect to JAK-STAT pathway,for diabetic nephropathy immunotherapy.Methods: in vivo:1? Type 2 diabetes mice model were established as follows: C57/BL6 mice were reared with high-fat diet for 8 weeks,and were injected with 30 mg/kg streptozotocin intraperitoneally After 8 weeks,the type2 diabetes nephropathy model was successfully set up and different drugs were administrated(insulin 1–2 U/day,benazepril 10 mg/kg per day intragastrically,IGF-1R inhibitor 30 mg/kg per day intragastrically).After 8 weeks of drugs administration,all mice were sacrificed kidney tissue,blood and urine samples were collected.2?Type 2diabetes rat model were established as follows: SD rats were reared with high-fat diet for 8 weeks,then were injected with 30 mg/kg streptozotocin intraperitoneally.When the model was successfully set up Insulin were administrated(3–5 U/day,).The blood,urine and kidney tissue samples were collected from at 4th,8th,12 th,16th weeks.3?inflammatory factor,JAK-STAT signal pathway protein and lipid metabolism markers were examined using immunohistochemistry and in situ hybridization.Results: The type 2 diabetes nephropathy model was built successfully with increased urinary protein excretion rate and increased inflammatory cell infiltration,and was characterized by increased CD68+,F4/80+cells,increased TLR4,?SMA,SR expression.IGF-1R inhibitors reversed this change,but benazepril and insulin treatment showed no significant changes.Insulin decreased the expression level of IGF-1,and increased the levels of suppressor of cytokine signaling 2(SOCS2).Benazepril and IGF-1R inhibitor treatment showed no significant changes,like insulin.In order to explain this,we set up rats model to explore the downstream signalings of IGF-1.Through literature reviewwe speculated that the attenuation of inflammation might be related to the change of JAK-STAT signal downstream of IGF-1.The expression of STAT5 in renal tissue was positively correlated with renal mass and VLDL(P < 0.05)at the age of 4 weeks;at the age of 8 weeks,the expression of STAT5 in renal tissue was positively correlated with renal mass,blood glucose,body weight,creatinine level,VLDL and PPAR.The expression of STAT5 was positively correlated with blood glucose,body weight,the level of urinary protein,urinary creatinine,urea nitrogen,VLDL,LDL and PPAR(P < 0.05)at 12 weeks-old,and with the level of urinary protein,urinary creatinine,urea nitrogen,VLDL,LDL and PPAR(P < 0.05)at 16 weeks-old.Conclusion: Thus inhibition of IGF-1R might be more effective than Ben or Ins in the anti-inflammation treatment of Diabetic nephropathy.The IGF1 R inhibitor blocked pathological changes induced by the over-expression of IGF1 in DN without up-regulating SOCS2 protein levels.Activation of the JAK-STAT signal pathway is consistent with the fat degeneration of the kidney.According to the correlation analysis,it may activate stat5-ppar pathway,resulting in increased expression of VLDL and aggravating renal impairment.