Abstract
Diabetic nephropathy (DN) is one of the major diabetic complications and the leading cause of end-stage renal disease. Abnormal angiogenesis results in new vessels that are often immature and play a pathological role in DN, contributing to renal fibrosis and disrupting glomerular failure. Purple corn has been utilized as a daily food and exerts disease-preventive activities. This study was designed to investigate whether anthocyanin-rich purple corn extract (PCE) prevented glomerular angiogenesis under hyperglycemic conditions. Human endothelial cells were cultured in conditioned media of mesangial cells exposed to 33 mM high glucose (HG-HRMC-CM). PCE decreased endothelial expression of vascular endothelial growth factor (VEGF) and hypoxia inducible factor (HIF)-1α induced by HG-HRMC-CM. Additionally, PCE attenuated the induction of the endothelial marker of platelet endothelial cell adhesion molecule (PECAM)-1 and integrin β3 enhanced in HG-HRMC-CM. Endothelial tube formation promoted by HG-HRMC-CM was disrupted in the presence of PCE. In the in vivo study employing db/db mice treated with 10 mg/kg PCE for 8 weeks, PCE alleviated glomerular angiogenesis of diabetic kidneys by attenuating the induction of VEGF and HIF-1α. Oral administration of PCE retarded the endothelial proliferation in db/db mouse kidneys, evidenced by its inhibition of the induction of vascular endothelium-cadherin, PECAM-1 and Ki-67. PCE diminished the mesangial and endothelial induction of angiopoietin (Angpt) proteins under hypeglycemic conditions. The induction and activation of VEGF receptor 2 (VEGFR2) were dampened by treating PCE to db/db mice. These results demonstrate that PCE antagonized glomerular angiogenesis due to chronic hyperglycemia and diabetes through disturbing the Angpt-Tie-2 ligand-receptor system linked to renal VEGFR2 signaling pathway. Therefore, PCE may be a potent therapeutic agent targeting abnormal angiogenesis in DN leading to kidney failure.
Highlights
The long-term complication of diabetes has been implicated as a major contributor to development and progression of pathologic microvascular changes [1,2]
This study examined whether HG-exposed mesangial cells facilitated expressions of proangiogenic factors in glomerular endothelial cells in a paracrine action, which was disrupted by purple corn extract (PCE)
7) PCE attenuated the proangiogenic induction of Angpt2, Tie-2 and Angpt1 in endothelial cells exposed to HG-HRMC-CM containing mesangial Angpt1
Summary
The long-term complication of diabetes has been implicated as a major contributor to development and progression of pathologic microvascular changes [1,2]. Diabetic nephropathy (DN) is one of the major diabetic complications and the leading cause of endstage kidney failure of which prevalence continues to increase [3,4]. A major feature of DN is microvasculature injury including glomerular hyperfiltration, renal injury and increased urinary albumin excretion, leading to glomerular dysfunction and renal failure [3,5]. The exact cause of DN is unknown, but hyperglycemia, advanced glycosylation products and activation of cytokines have been postulated as various mechanisms [6]. Hyperglycemia-mediated endothelial injury may predispose to albuminuria in diabetes directly and through a communication with neighboring mesangial cells and podocytes [7].
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