Tie2 activator 4E2 ameliorates diabetic nephropathy and synergizes with dapagliflozin in a mouse model

Diabetic nephropathy (DN), a primary cause of end-stage renal disease, stems from hyperglycemia-induced vascular dysfunction and aberrant angiogenesis. Sodium-glucose cotransporter 2 inhibitors, such as dapagliflozin, improve glycemic control and provide renal protection yet fall short of fully halting DN progression. This study explores 4E2, a Tie2 receptor activator that mimics angiopoietin-1 to stabilize the vascular endothelium, as a novel DN therapy-both independently and in combination with dapagliflozin. In a streptozotocin (STZ)-induced DN mouse model (DBA/2J strain), male mice were treated with weekly intravenous 4E2, daily oral dapagliflozin, or a combination of both for 4 weeks following STZ administration. Dapagliflozin primarily reduced fasting blood glucose with modest renoprotective effects, whereas 4E2 significantly lowered kidney weight, blood urea nitrogen, and urinary albumin while elevating serum albumin, indicating greater renal protection. Histological analysis showed that 4E2 more effectively attenuated glomerular hypertrophy and lesions compared to dapagliflozin. Immunohistochemistry revealed that 4E2 markedly increased VE-cadherin and CD31 expression while decreasing PDGFR-β, reflecting enhanced endothelial stability and reduced vascular remodeling through Tie2-mediated mechanisms. Combination therapy synergistically enhanced these outcomes, achieving superior reductions in glucose levels, glomerular damage, and vascular pathology compared to either treatment alone. In contrast to anti-VEGF therapies, which can worsen proteinuria, 4E2-mediated Tie2 activation normalizes vascular stability without disrupting physiological angiogenesis, providing a safer therapeutic option. These findings establish 4E2 as a promising treatment for DN, especially when combined with dapagliflozin, by leveraging Tie2-driven stabilization and synergistic benefits to meet this critical unmet need.