Comparation of the effects of insulin-like growth factor-1 receptor inhibitor and insulin on renal interstitial macrophage infiltration in mice with type 2 diabetic kidney disease / 中华肾脏病杂志

ABSTRACT

Objective@#To compare the effect of insulin-like growth factor-1 receptor (IGF-1R) inhibitor and insulin on renal interstitial macrophage infiltration in mice with type 2 diabetic kidney disease (DKD) mice.@*Methods@#Twenty-four male C57BL/6 mice were selected. After 1 week of adaptive feeding, 6 rats were randomly selected as the control group. The other mice were intraperitoneally injected with streptozotocin (30 mg/kg) after 8 weeks of high-fat and high-sugar feeding. After 72 h, the type 2 diabetes mellitus (DM) models were successfully established if random blood glucose was greater than 16.7 mmol/L. After 8 weeks, if the proteinuria of DM mice increased, the DKD models were successful. DKD mice were divided into 3 groups by random number remainder method: DKD group (n=6), DKD+insulin group (insulin group, n=6, subcutaneous injection of 1-2 U/d insulin) and DKD+IGF-1R inhibitor (IGF-1R inhibitor group, n=6, administered with 30 mg·kg-1·d-1 IGF-1R inhibitor). They were continuously treated for 8 weeks. Random blood glucose was tested by glucometer. Blood and urine were collected, and biochemical indicators, such as serum creatinine, urea nitrogen and urine protein were measured by biochemical analyzer. Renal pathological changes were detected by hematoxylin-eosin staining (HE) and periodic acid-schiff staining (PAS). Suppressor of cytokine signaling 2 (SOCS2) mRNA and insulin-like growth factor-1 (IGF-1) mRNA were detected by in situ hybridization. The protein expressions of SOCS2, F4/80, Toll-like receptor 4 (TLR4) and CD68 were detected by immunohistochemistry.@*Results@#Compared with the control group, blood glucose, serum creatinine, serum urea nitrogen and urinary protein excretion rate were significantly higher in DKD mice (all P<0.05), and CD68+ cells number, F4/80+ cells number and the expression of TLR4 in the tubulointerstitial of DKD mice were significantly higher (all P<0.05). After intervention with insulin or IGF-1R inhibitor, serum creatinine, serum urea nitrogen and urinary protein excretion rate of DKD mice were significantly reduced (all P<0.05). Insulin intervention could significantly reduce blood glucose in mice (P<0.05), but had no significant effect on macrophages. Although IGF-1R inhibitor did not significantly reduce blood glucose, it could significantly reduce the number of CD68, F4/80 positive cells and the expression of TLR4 protein in renal interstitium of DKD mice (all P<0.05). Compared with the DKD group, insulin intervention significantly reduced the expression of IGF-1 protein and mRNA (both P<0.01), and increased the expression of SOCS2 mRNA and protein (both P<0.01). And the expression of SOCS2 protein was correlated with the number of F4/80+ cells in insulin group (R2=0.8461, P=0.005). However, IGF-1R inhibitors had no significant effect on SOCS2 expression, but had better inhibition of macrophage infiltration.@*Conclusion@#IGF-1R inhibitor has a better inhibitory effect on DKD renal interstitial macrophage infiltration than insulin. The mechanism may be related to the fact that IGF-1R inhibitor does not up-regulate SOCS2 expression, whereas insulin up-regulates SOCS2 expression to activate some potential pathways.