Syndecan-4 Knockout Leads to Reduced Extracellular Transglutaminase-2 and Protects against Tubulointerstitial Fibrosis
Syndecan-4 Knockout Leads to Reduced Extracellular Transglutaminase-2 and Protects against Tubulointerstitial Fibrosis
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DOI：
10.1681/asn.2013050563
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发表时间：
2014-05-01
影响因子：
13.6
通讯作者：
Verderio, Elisabetta A. M.
中科院分区：
文献类型：
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作者：
Scarpellini, Alessandra;Huang, Linghong;Verderio, Elisabetta A. M.
丙酮酸是能量代谢的关键中间体，可以发挥抗氧化和抗炎作用。然而，丙酮酸在阿基期间的命运仍然未知。在此，我们评估了单侧缺血（15-60分钟; 0-18小时血管回流）或甘油诱导的ARF小鼠的肾皮质丙酮酸及其主要决定因素（糖酵解、糖原合成、丙酮酸脱氢酶[PDH]和H2 O2水平）。还讨论了可通过乳酸脱氢酶转化回丙酮酸的缺血后乳酸的命运。缺血和甘油各自诱导持续的丙酮酸消耗。在缺血期间，丙酮酸水平降低与乳酸水平升高相关。在早期再灌注期间，丙酮酸水平仍然受到抑制，但乳酸水平低于对照水平，可能是由于肾乳酸快速流出。在晚期再灌注和甘油诱导的阿基期间，丙酮酸消耗对应于增加的再生（丙酮酸消耗）。丙酮酸盐注射增加阿基中肾皮质葡萄糖含量而不是正常肾脏的观察结果强调了这一发现。阿基降低PDH水平，可能限制丙酮酸转化为乙酰辅酶A。值得注意的是，丙酮酸盐治疗减轻了阿基的严重程度。这种肾保护作用与细胞保护性血红素加氧酶1和IL-10 mRNA的增加、促炎性mRNA的选择性减少（例如，MCP-1和TNF-α），并改善组织ATP水平。特别是，丙酮酸增加皮质H2 O2水平。我们的结论是，阿基诱导肾皮质丙酮酸的深刻和持久的消耗，这可能会引起额外的损伤。
Pyruvate is a key intermediary in energy metabolism and can exert antioxidant and anti-inflammatory effects. However, the fate of pyruvate during AKI remains unknown. Here, we assessed renal cortical pyruvate and its major determinants (glycolysis, gluconeogenesis, pyruvate dehydrogenase [PDH], and H2O2 levels) in mice subjected to unilateral ischemia (15-60 minutes; 0-18 hours of vascular reflow) or glycerol-induced ARF. The fate of postischemic lactate, which can be converted back to pyruvate by lactate dehydrogenase, was also addressed. Ischemia and glycerol each induced persistent pyruvate depletion. During ischemia, decreasing pyruvate levels correlated with increasing lactate levels. During early reperfusion, pyruvate levels remained depressed, but lactate levels fell below control levels, likely as a result of rapid renal lactate efflux. During late reperfusion and glycerol-induced AKI, pyruvate depletion corresponded with increased gluconeogenesis (pyruvate consumption). This finding was underscored by observations that pyruvate injection increased renal cortical glucose content in AKI but not normal kidneys. AKI decreased PDH levels, potentially limiting pyruvate to acetyl CoA conversion. Notably, pyruvate therapy mitigated the severity of AKI. This renoprotection corresponded with increases in cytoprotective heme oxygenase 1 and IL-10 mRNAs, selective reductions in proinflammatory mRNAs (e.g., MCP-1 and TNF-alpha), and improved tissue ATP levels. Paradoxically, pyruvate increased cortical H2O2 levels. We conclude that AKI induces a profound and persistent depletion of renal cortical pyruvate, which may induce additional injury.