Reduction in VEGF Protein and Phosphorylated Nephrin Associated with Proteinuria in Adriamycin Nephropathy Rats

Abstract

Background/Aims: The relationship between vascular endothelial growth factor (VEGF) and the phosphorylated critical podocyte slit diaphragm molecule nephrin is not fully clarified. This study investigated the dynamic changes in VEGF expression and nephrin phosphorylation, and the effects of the antiproteinuric drugs prednisone and lisinopril on them in Adriamycin nephropathy rats. Methods: Renal tissues from Adriamycin rats were collected at days 3, 7, 14, and 28. Distribution and expression of VEGF was revealed by immunohistochemistry, real-time PCR and Western blot. Phosphorylated nephrin was evaluated by immunoprecipitation. Results: A discontinuous redistribution of VEGF was displayed at day 3, followed by significant protein reduction at day 7 with persistent downregulation to day 28. Phosphorylated nephrin decreased evidently at day 14 and persisted to day 28. The reduction in VEGF and phosphorylated nephrin was not a result of podocyte loss. The intervention of prednisone and lisinopril evidently reduced proteinuria, effectively attenuated the severe lesions of podocyte foot processes, and restored the reduction in VEGF and nephrin phosphorylation. At day 28, the reduction in VEGF and phosphorylated nephrin was negatively correlated with proteinuria, whereas the phosphorylated nephrin was positively correlated with VEGF protein from day 7 to day 28. Conclusion: The reduction in VEGF protein and nephrin phosphorylation was possibly involved in the proteinuria in Adriamycin rats, and there might be some relationship between VEGF and nephrin phosphorylation. The antiproteinuric effects of lisinopril and prednisone were achieved at least partially by restoring VEGF protein and nephrin phosphorylation.

Oxidative/Nitrative Stress and Inflammation Drive Progression of Doxorubicin-Induced Renal Fibrosis in Rats as Revealed by Comparing a Normal and a Fibrosis-Resistant Rat Strain

“…Glomerular structural changes develop in a well predictable manner: altered mRNA levels of nephrin, podocyn and NEPH1, and swelling of the foot-processes are present at day 7 [37]. Podocyte swelling with cytoplasmic vesicles appear at day 14, and finally widespread podocyte foot process fusion at day 28 [38]. As a marker of glomerular filtration barrier damage, proteinuria develops [39].…”

Induction of Podocyte VEGF164 Overexpression at Different Stages of Development Causes Congenital Nephrosis or Steroid-Resistant Nephrotic Syndrome

“…24,47 Dexamethasone promotes nephrin trafficking by stimulating glycosylation and release from the endoplasmic reticulum in HEK cells transfected with human nephrin 48 and improves nephrin expression in puromycin aminonucleoside and adriamycin-induced nephrosis. 49,50 Glucocorticosteroids are known to function as negative regulators of VEGF transcription and secretion in vitro. 23,49,51 In children with steroid-sensitive nephrotic syndrome, whose serum and urine VEGF levels were elevated, glucocorticosteroid treatment reduced VEGF levels.…”

Off the Beaten Renin–Angiotensin–Aldosterone System Pathway: New Perspectives on Antiproteinuric Therapy

“…In human podocytes and rodent adriamycin nephrosis, dexamethasone was shown to restore suppressed nephrin and reduced vascular endothelial growth factor (VEGF) proteins. 7,8 Nephrin is an integral component of the slit diaphragm structure; when reduced in quantity, as in nephrotic syndrome, it causes disruption of the glomerular barrier. VEGF is involved in angiogenesis regulation.…”