Hyperphosphatemia-Induced Oxidant/Antioxidant Imbalance Impairs Vascular Relaxation and Induces Inflammation and Fibrosis in Old Mice

Abstract

Aging impairs vascular function, but the mechanisms involved are unknown. The aim of this study was to analyze whether aging-related hyperphosphatemia is implied in this effect by elucidating the role of oxidative stress. C57BL6 mice that were aged 5 months (young) and 24 months (old), receiving a standard (0.6%) or low-phosphate (0.2%) diet, were used. Isolated mesenteric arteries from old mice showed diminished endothelium-dependent vascular relaxation by the down-regulation of NOS3 expression, increased inflammation and increased fibrosis in isolated aortas, compared to those isolated from young mice. In parallel, increased Nox4 expression and reduced Nrf2, Sod2-Mn and Gpx1 were found in the aortas from old mice, resulting in oxidant/antioxidant imbalance. The low-phosphate diet improved vascular function and oxidant/antioxidant balance in old mice. Mechanisms were analyzed in endothelial (EC) and vascular smooth muscle cells (SMCs) treated with the phosphate donor ß-glycerophosphate (BGP). In EC, BGP increased Nox4 expression and ROS production, which reduced NOS3 expression via NFκB. BGP also increased inflammation in EC. In SMC, BGP increased Collagen I and fibronectin expression by priming ROS production and NFκB activity. In conclusion, hyperphosphatemia reduced endothelium-dependent vascular relaxation and increased inflammation and vascular fibrosis through an impairment of oxidant/antioxidant balance in old mice. A low-phosphate diet achieved improvements in the vascular function in old mice.

Malting barley carbon dots-mediated oxidative stress promotes insulin resistance in mice via NF-κB pathway and MAPK cascade

“…The inflammatory cytokine, TNFα, can directly phosphorylate insulin receptor substrates-1 (IRS-1) at Ser307 [ 50 , 51 ], leading to the inhibition of insulin signaling, which in turn inhibits the phosphorylated protein of protein kinase B (AKT) at Ser473, resulting in IR. In addition, TNFα can also indirectly block insulin signaling by activating the mitogen-activated protein kinase (MAPK) cascade, leading to phosphorylation of p38 MAPK and c-Jun N-terminal kinase (JNK), which also contributes to phosphorylation of IRS1 (Ser307) [ 52 ].…”

The structure of mineral and bone disorders in patients with сhronic kidney disease of the 5th dialysis stage, taking into account the presence or absence of a diagnosis of type 1 diabetes mellitus

“…Гиперфосфатемия снижает эндотелий-зависимую релаксацию сосудов и усиливает воспаление и сосудистый фиброз из-за нарушения баланса AGE/RAGE, снижает антиоксидантные эффекты. Диета с низким содержанием фосфатов, применение фосфат-биндеров и, в итоге, нормализация уровня фосфора приводят к улучшению сосудистой функции [42].…”

Accelerated Vascular Aging in Chronic Kidney Disease: The Potential for Novel Therapies

“…The pathological process is further compounded by depletion of calcification inhibitors and poor vitamin K status.11,70 In addition to its established procalcifying effects in CKD, phosphate drives a multitude of detrimental outcomes in the vasculature, such as endothelial cell senescence,71 vasoconstriction and endothelial dysfunction 72. Furthermore, aged mice on a high phosphate diet demonstrate impaired endothelium-dependent vasorelaxation, which associates with increased expression of inflammatory and fibrotic markers in endothelial and VSMC cells 73…”

“…72 Furthermore, aged mice on a high phosphate diet demonstrate impaired endothelium-dependent vasorelaxation, which associates with increased expression of inflammatory and fibrotic markers in endothelial and VSMC cells. 73…”

“…of inflammatory and fibrotic markers in endothelial and VSMC cells. 73 The long-term effects of kidney transplantation on VC remain the subject of debate. Although short-term studies have demonstrated that coronary artery calcification may be reversed after kidney transplantation, longer-term studies have shown increased coronary artery calcification post kidney transplantation, suggesting restoration of renal function may not be enough to reverse VC.…”