Suramin enhances the urinary excretion of VEGF-A in normoglycemic and streptozotocin-induced diabetic rats

Abstract

Background Vascular endothelial growth factor A (VEGF-A) and P2-receptors (P2Rs) are involved in the pathogenesis of diabetic nephropathy. The processing of VEGF-A by matrix metalloproteinases (MMP) regulates its bioavailability. Since the ATP-induced release of MMP-9 is mediated by P2Rs, we investigated the effect of suramin on VEGF-A excretion in urine and the urinary activity of total MMP and MMP-9. Methods The effect of suramin (10 mg/kg, ip) on VEGF-A concentration in serum and its excretion in urine was investigated in streptozotocin (STZ)-induced diabetic rats over a 21-day period. The rats received suramin 7 and 14 days after a single STZ injection (65 mg/kg, ip). A 24-h collection of urine was performed on the day preceding the administration of STZ and the first administration of suramin and on the day before the end of the experiment. The VEGF-A in serum and urine, albumin in urine, and total activity of MMP and MMP-9 in urine were measured using immunoassays. Results Diabetic rats are characterized by a sixfold higher urinary excretion of VEGF-A. Suramin potentiates VEGF-A urinary excretion by 36% (p = 0.046) in non-diabetic and by 75% (p = 0.0322) in diabetic rats but it did not affect VEGF-A concentration in the serum of non-diabetic and diabetic rats. Urinary albumin excretion as well as total MMP and MMP-9 activity was increased in diabetic rats, but these parameters were not affected by suramin. Conclusion Suramin increases the urinary excretion of VEGF-A in normoglycemia and hyperglycaemia, possibly without the involvement of MMP-9. Suramin may be used as a pharmacological tool enhancing VEGF-A urinary secretion.

Long-Term Effects of Suramin on Renal Function in Streptozotocin-Induced Diabetes in Rats

“…In addition, it is likely that suramin may modify the progression of DN by altering VEGF-A binding to receptors. Consistent with this, our previous studies in short-term streptozotocin-induced diabetes showed that suramin affects renal VEGF-A with specific receptors and renal arteries' response to acetylcholine [20,21]. In addition, suramin has been shown to reduce fibrosis and improve renal function, such as reducing proteinuria, in experimental diabetes [22][23][24].…”

“…With an incomplete understanding of late events in the pathogenesis of DN, we decided to use the long-term streptozotocin-induced diabetes model to investigate the role of VEGF-A in the late stages of the disease. In addition, we used suramin as a pharmacological tool to potentially modify VEGF-A expression or concentration, as we have previously shown that suramin in short-term diabetes increases urinary excretion of VEGF-A without altering its blood concentration [20]. We measured the concentration of VEGF-A in the blood and its excretion in the urine, and both parameters were elevated.…”

Integrated Bioinformatics and Clinical Correlation Analysis of Key Genes, Pathways, and Potential Therapeutic Agents Related to Diabetic Nephropathy

“…Therefore, proper VEGFA level is of great significance for maintaining normal glomerular function. Although some studies have found that there is a higher VEGFA level in diabetes, suggesting that the elevated VEGFA levels are pathogenic markers for diabetes [ 19 ]. However, VEGFA knock out diabetic mice has adverse consequences characterized by global sclerosis and death [ 18 ] which illustrate the opinion that the upregulation of VEGFA in diabetic kidneys may protect the microvasculature from injury and reduction of VEGFA in diabetes may be harmful.…”

A Network Pharmacology Approach to Understand the Action Mechanisms of the TangShenKangPing Decoction for Diabetic Nephropathy Treatment

“…[27] The NLRP3 inflammasome has been linked to the development of various kidney diseases, including acute kidney injury (AKI), chronic kidney diseases (CKD), and DN. [28] Anti-vascular endothelial growth factor (VEGF) antibodies reduce hyperosmolarity and proteinuria in diabetic rats, [29] and VEGF is an important component of DN angiogenesis. [28,30] Consequently, we chose three exemplary genes from the aforementioned list of 37 prospective therapeutic target genes for DN to determine their usefulness in the treatment of DN.…”