Inhibitor of IGF1 receptor alleviates the inflammation process in the diabetic kidney mouse model without activating SOCS2

Objective:
To investigate the anti-inflammatory mechanism of an IGF1R inhibitor in the treatment of diabetic nephropathy.

Methods:
C57BL/6 mice were fed a high-fat diet for 8 weeks, followed by intraperitoneal injection of streptozotocin (30 mg/kg) to induce type 2 diabetes. After another 8 weeks, a diabetic nephropathy model was established. Diabetic mice were then treated for 8 weeks with one of the following: insulin (1–2 U/day, subcutaneously), benazepril (10 mg/kg/day, orally), or an IGF1R inhibitor (30 mg/kg/day, orally). At the end of the treatment period, kidney tissues were collected for analysis. Inflammatory markers (F4/80, TLR4, CD68) and fibrosis-related proteins (α-SMA, E-cadherin, SR) were evaluated using immunohistochemistry and in situ hybridization.

Results:
The diabetic nephropathy model was successfully established, as evidenced by increased urinary protein excretion and heightened inflammatory cell infiltration. Elevated levels of CD68⁺ and F4/80⁺ cells, along with increased expression of TLR4, α-SMA, and SR, were observed in diabetic kidneys. Treatment with the IGF1R inhibitor significantly reduced these pathological changes, whereas benazepril and insulin had limited effects. Insulin treatment was associated with decreased IGF-1 expression and increased levels of suppressor of cytokine signaling 2 (SOCS2), a response not observed with benazepril or IGF1R inhibition.

Conclusion:
IGF1R inhibition effectively attenuates inflammation and fibrosis in diabetic kidney disease (DKD) and offers superior anti-inflammatory benefits compared to benazepril or insulin. This therapeutic effect appears to be mediated by suppression of IGF1-driven pathology without upregulation of SOCS2, highlighting IGF1R inhibition GSK1904529A as a promising strategy for managing DKD.