VEGF-A: A Novel Mechanistic Link Between CYP2C-Derived EETs and Nox4 in Diabetic Kidney Disease

Abstract

Diabetes is associated with decreased epoxyeicosatrienoic acids (EET) bioavailability and increased levels of glomerular vascular endothelial growth factor A (VEGF-A) expression. We examined whether a soluble epoxide hydrolase (sEH) inhibitor protects against pathologic changes in diabetic kidney disease and whether the inhibition of VEGF-A signaling pathway attenuates diabetes-induced glomerular injury. We also aimed to delineate the crosstalk between cytochrome P450 2C (CYP2C)-derived EETs and VEGF-A. Streptozotocin (STZ)-induced type 1 diabetic (T1D) rats were treated with 25 mg/L of AUDA in drinking water for 6 weeks. In parallel experiments, T1D rats were treated with either SU5416 or humanized monoclonal anti-VEGF-A neutralizing antibody for 8 weeks. Following treatment, the rats were euthanized, and kidney cortices were isolated for further analysis. Treatment with AUDA attenuated the diabetes-induced decline in kidney function. Furthermore, treatment with AUDA decreased diabetes-associated oxidative stress and NADPH oxidase activity. Interestingly, the downregulation of CYP2C11-derived EET formation is found to be correlated with the activation of VEGF-A signaling pathway. In fact, inhibiting VEGF-A using anti-VEGF or SU5416 markedly attenuated diabetes-induced glomerular injury through the inhibition of Nox4-induced ROS production. These findings were replicated in vitro in rat and human podocytes cultured in a diabetic milieu. Taken together, our results indicate that hyperglycemia-induced glomerular injury is mediated by the downregulation of CYP2C11-derived EET formation, followed by the activation of the VEGF-A signaling and upregulation of Nox4. To our knowledge, this is the first study to highlight VEGF-A as a mechanistic link between CYP2C11-derived EET production and Nox4.

Endothelial dysfunction in vascular complications of diabetes: a comprehensive review of mechanisms and implications

“…NOX1 and NOX4 were upregulated in aortas and mesenteric arteries of T2DM mice (26). Enhanced NOX4 activity and expression were also found in rats with type 1 diabetes (27). Both may lead to an increase in ROS.…”

“…Ang-(1-7) treatment also attenuated the elevation of renal NOX activity in the kidneys of diabetic spontaneously hypertensive rats, reducing the degree of hyperglycemia. It significantly prevented the diabetes-induced reduction in catalase activity, as well as the reduction in PPARgamma mRNA and protein levels in vitro (27,29). High levels of ROS generation or low antioxidant activity can result in endothelial mitochondria dysfunction (30).…”

Oxidative Stress: A Culprit in the Progression of Diabetic Kidney Disease

“…EETs possess anti-inflammatory, anti-apoptotic, pro-angiogenic, and anti-hypertensive properties within the cardiovascular system, indicating a potential therapeutic role in the development of DKD. The research indicates that glomerular injury caused by hyperglycemia is triggered by a decrease in cytochrome P450 2C11 (CYP2C11)-derived EET formation [60]. This reduction in EETs subsequently leads to the activation of vascular endothelial growth factor A (VEGF-A) signaling and an increase in Nox4 expression.…”