VEGFC Reduces Glomerular Albumin Permeability and Protects Against Alterations in VEGF Receptor Expression in Diabetic Nephropathy

Abstract

Elevated levels of vascular endothelial growth factor (VEGF) A are thought to cause glomerular endothelial cell (GEnC) dysfunction and albuminuria in diabetic nephropathy. We hypothesized that VEGFC could counteract these effects of VEGFA to protect the glomerular filtration barrier and reduce albuminuria. Isolated glomeruli were stimulated ex vivo with VEGFC, which reduced VEGFA- and type 2 diabetes–induced glomerular albumin solute permeability (Ps’alb). VEGFC had no detrimental effect on glomerular function in vivo when overexpression was induced locally in podocytes (podVEGFC) in otherwise healthy mice. Further, these mice had reduced glomerular VEGFA mRNA expression, yet increased glomerular VEGF receptor heterodimerization, indicating differential signaling by VEGFC. In a model of type 1 diabetes, the induction of podVEGFC overexpression reduced the development of hypertrophy, albuminuria, loss of GEnC fenestrations and protected against altered VEGF receptor expression. In addition, VEGFC protected against raised Ps’alb by endothelial glycocalyx disruption in glomeruli. In summary, VEGFC reduced the development of diabetic nephropathy, prevented VEGF receptor alterations in the diabetic glomerulus, and promoted both glomerular protection and endothelial barrier function. These important findings highlight a novel pathway for future investigation in the treatment of diabetic nephropathy.

Blocking matrix metalloproteinase-mediated syndecan-4 shedding restores the endothelial glycocalyx and glomerular filtration barrier function in early diabetic kidney disease

“…24,27 Moreover, vascular endothelial growth factor C also protected against raised glomerular permeability and ameliorated glycocalyx disruption in diabetic glomeruli. 41 Blockade of MMP2 and -9 attenuated diabetes-induced changes in glomerular endothelial glycocalyx Sdc4 and glomerular SDC4 at the mRNA and protein levels, suggesting a reduction in glomerular endothelial SDC4 shedding. We previously observed similar effects in human GEC, where MMP inhibition attenuated Sdc4 mRNA synthesis and SDC4 shedding, resulting in a reduction in Ps'alb.…”

“…Our findings are consistent with our previous work showing that at 8 weeks post-STZ injection, type 1 diabetic mice do not develop GBM thickness and podocyte effacement. 41 GBM thickening has been reported in some but not all mouse models of diabetic nephropathy. 42 For example, GBM thickening occurs in diabetic DBA2J mice after w25 weeks of hyperglycemia.…”

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

“…In line with this, a recent study revealed that upregulation of VEGFA 165 b isoform in mouse podocytes in vivo protects against diabetic kidney injury and albuminuria by phosphorylating VEGF receptor 2 in endothelial cells and restoring the endothelial glycocalyx damaged by diabetes . 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.…”

Exploring the Mechanisms Underlying the Therapeutic Effect of Salvia Miltiorrhiza Against Diabetic Nephropathy Using Network Pharmacology and Molecular Docking

“…It is an important gene in the immune in ammatory mechanism of DN [ 35 ]. It is closely related to mesangial matrix proliferation, basement membrane thickening, podocyte damage, and renal tubular epithelial cell transdifferentiation [ 36 ]; IL6 and TNF have immunomodulatory and proin ammatory effects [ 37 ]; VEGFA is related to the vascular permeability of patients with DN [ 38 ]; the activation of EGFR upregulates the production of ROS and endoplasmic reticulum stress, and the onset of DN plays an important role in this mechanism [ 39 ]. Therefore, it can be inferred that luteolin, tanshinone IIA, and salvianolic acid B, the main components of salvianolic acid B, can reduce oxidative stress and inhibit the expression of in ammatory mediators such as IL-10, IL-6, TNF, etc., thus delaying DN progression.…”