Vascular calcification (VC) is a major cause of mortality in patients with chronic kidney disease (CKD). While elevations in serum phosphorus contribute to VC, we provide evidence here for a major role of oxidative stress (OS) in VC pathogenesis without an apparent increase in serum phosphorus in early CKD. In a rat model for stage 5 CKD (CKD5), we observed 1) robust increases of VC and OS, 2) significant reductions of smooth muscle 22 alpha (SM22α) and calponin, and 3) upregulations in Runt-related transcription factor 2 (RUNX2) and collagen I in vascular smooth muscle cells (VSMCs). Inhibition of OS using MnTMPyP dramatically reduced these events without normalization of hyperphosphatemia. In CKD5 patients with VC (n = 11) but not in those without VC (n = 13), OS was significantly elevated. While the serum levels of calcium and phosphate were not altered in the animal model for early stage CKD (ECKD), OS, VC, SM22α, calponin, RUNX2, collagen I and NADPH oxidase 1 (NOX1) in VSMCs were all significantly changed. More importantly, serum (5%) derived from patients with ECKD (n = 30) or CKD5 (n = 30) induced SM22α and calponin downregulation, and RUNX2, collagen I, NOX1 upregulation along with a robust elevation of OS and calcium deposition in primary rat VSMCs. These alterations were all reduced by MnTMPyP, ML171 (a NOX1 inhibitor), and U0126 (an inhibitor of Erk signaling). Collectively, we provide a comprehensive set of evidence supporting an important role of OS in promoting VC development in CKD patients (particularly in those with ECKD); this was at least in part through induction of osteoblastic transition in VSMCs which may involve the Erk singling. Our research thus suggests that reductions in OS may prevent VC in CKD patients.

中文翻译：

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氧化应激有助于慢性肾脏病患者的血管钙化。

血管钙化（VC）是慢性肾脏病（CKD）患者死亡的主要原因。虽然血清磷的升高有助于VC，但我们在此提供了氧化应激（OS）在VC发病机理中的主要作用而早期CKD中血清磷没有明显增加的证据。在5期CKD（CKD5）的大鼠模型中，我们观察到1）VC和OS的强劲增加，2）平滑肌22 alpha（SM22α）和钙蛋白的显着降低，以及3）Runt相关转录因子2的上调（ RUNX2）和血管平滑肌细胞（VSMC）中的胶原蛋白I。使用MnTMPyP抑制OS可以显着减少这些事件，而无需高磷酸盐血症的正常化。在患有VC的CKD5患者中（n = 11），但在没有VC的患者中（n = 13），OS明显升高。在早期CKD（ECKD）的动物模型中，尽管血清钙和磷酸盐水平没有改变，但VSMC中的OS，VC，SM22α，钙蛋白，RUNX2，I型胶原和NADPH氧化酶1（NOX1）均发生了显着变化。更重要的是，来自患有ECKD（n = 30）或CKD5（n = 30）的患者的血清（5％）诱导SM22α和钙蛋白的下调，以及RUNX2，I型胶原，NOX1的上调以及OS和钙沉积的强烈升高。原代大鼠VSMC。MnTMPyP，ML171（一种NOX1抑制剂）和U0126（一种Erk信号抑制剂）都减少了这些改变。我们集体提供了一组综合证据，支持OS在促进CKD患者（尤其是患有ECKD的患者）的VC发展中的重要作用；这至少部分是由于在VSMC中诱导成骨细胞转变，可能涉及Erk单一。因此，我们的研究表明OS的降低可能会阻止CKD患者的VC。