Antiangiogenic Therapy for Diabetic Nephropathy

Abstract

Angiogenesis has been shown to be a potential therapeutic target for early stages of diabetic nephropathy in a number of animal experiments. Vascular endothelial growth factor (VEGF) is the main mediator for abnormal angiogenesis in diabetic glomeruli. Although beneficial effects of anti-VEGF antibodies have previously been demonstrated in diabetic animal experiments, recent basic and clinical evidence has revealed that the blockade of VEGF signaling resulted in proteinuria and renal thrombotic microangiopathy, suggesting the importance of maintaining normal levels of VEGF in the kidneys. Therefore, antiangiogenic therapy for diabetic nephropathy should eliminate excessive glomerular angiogenic response without accelerating endothelial injury. Some endogenous antiangiogenic factors such as endostatin and tumstatin inhibit overactivation of endothelial cells but do not specifically block VEGF signaling. In addition, the novel endothelium-derived antiangiogenic factor vasohibin-1 enhances stress tolerance and survival of the endothelial cells, while inhibiting excess angiogenesis. These factors have been demonstrated to suppress albuminuria and glomerular alterations in a diabetic mouse model. Thus, antiangiogenic therapy with promising candidates will possibly improve renal prognosis in patients with early stages of diabetic nephropathy.

SHIPping out diabetes—Metformin, an old friend among new SHIP2 inhibitors

“…In experimental diabetes, VEGFC enhances the synthesis of endothelial glycocalyx and reduces albumin permeability in glomeruli, and thereby reduces the development of diabetic kidney injury . While animal experiments have suggested promise for antiangiogenic therapies, and especially for anti‐VEGF antibodies for treating DKD, findings in human, demonstrating development of renal injury and proteinuria as summarized in a recent review, have raised a concern about blocking VEGF signalling. Concomitantly, it appears that either too much or too little of VEGFA can lead to pathological changes in the kidney .…”

“…While animal experiments have suggested promise for antiangiogenic therapies, and especially for anti‐VEGF antibodies for treating DKD, findings in human, demonstrating development of renal injury and proteinuria as summarized in a recent review, have raised a concern about blocking VEGF signalling. Concomitantly, it appears that either too much or too little of VEGFA can lead to pathological changes in the kidney . Interestingly, inhibition of VEGFB signalling in experimental DKD models appears to protect against DKD— via non‐angiogenic mechanisms—by ameliorating renal lipotoxicity and thereby reducing pathological changes in the kidney, sensitizing podocytes to insulin and preventing renal dysfunction …”

Calcium dobesilate reduces VEGF signaling by interfering with heparan sulfate binding site and protects from vascular complications in diabetic mice

“…Further studies are however required to demonstrate the effectiveness of CaD in the treatment of peripheral DNP. Since CaD pharmacokinetics is already know [63], and it is currently used to treat vascular complications of diabetic retinopathy [64], our findings demonstrated the therapeutic potential of CaD in the early stages of DN given that at present, anti-VEGF antibody or tyrosine kinase inhibitors therapy for diabetic nephropathy is not warranted [65].…”

Calcium dobesilate reduces VEGF signaling by interfering with heparan sulfate binding site and protects from vascular complications in diabetic mice

“…Further studies are required to demonstrate the effectiveness of CaD in the treatment of peripheral diabetic neuropathy. Since CaD pharmacokinetics is already know (48), and it is currently used to treat vascular complications of diabetic retinopathy (49), our findings demonstrated the therapeutic potential of CaD in the early stages of DN given that at present, anti-VEGF antibody or tyrosine kinase inhibitors therapy for diabetic nephropathy is not warranted (50).…”