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首页> 外文期刊>American Journal of Physiology >High-mobility group box 1 inhibits HCO3 absorption in medullary thick ascending limb through a basolateral receptor for advanced glycation end products pathway
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High-mobility group box 1 inhibits HCO3 absorption in medullary thick ascending limb through a basolateral receptor for advanced glycation end products pathway

机译：高迁移率组箱1通过用于先进的糖糖末端产品途径的基底外侧受体抑制HCO3厚度上升肢体中的吸收

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摘要

High-mobility group box 1 (HMGB1) is a damage-associated molecule implicated in mediating kidney dysfunction in sepsis and sterile inflammatory disorders. HMGB1 is a nuclear protein released extracellularly in response to infection or injury, where it interacts with Toll-like receptor 4 (TLR4) and other receptors to mediate inflammation. Previously, we demonstrated that LPS inhibits HCO3" absorption in the medullary thick ascending limb (MTAL) through a basolateral TLR4-ERK pathway (Watts BA III, George T, Sherwood ER, Good DW. Am J Physiol Cell Physiol 301: C1296-C1306, 2011). Here, we examined whether HMGB1 could inhibit HCO3" absorption through the same pathway. Adding HMGB1 to the bath decreased HCO^ absorption by 24% in isolated, perfused rat and mouse MTALs. In contrast to LPS, inhibition by HMGB1 was preserved in MTALs from TLR4~7~ mice and was unaffected by ERK inhibitors. Inhibition by HMGB1 was eliminated by the receptor for advanced glycation end products (RAGE) antagonist FPS-ZM1 and by neutralizing anti-RAGE antibody. Confocal immunofluorescence showed expression of RAGE in the basolateral membrane domain. Inhibition of HCOJ absorption by HMGB1 through RAGE was additive to inhibition by LPS through TLR4 and to inhibition by Gram-positive bacterial molecules through TLR2. Bath amiloride, which selectively prevents inhibition of MTAL HCO^ absorption mediated through Na+/H+ exchanger 1 (NHE1), eliminated inhibition by HMGB1. We conclude that HMGB1 inhibits MTAL HCOJ absorption through a RAGE-dependent pathway distinct from TLR4-mediated inhibition by LPS. These studies provide new evidence that HMGB1-RAGE signaling acts directly to impair the transport function of renal tubules. They reveal a novel paradigm for sepsis-induced renal tubule dysfunction, whereby exogenous pathogen-associated molecules and endogenous damage-associated molecules act directly and independently to inhibit MTAL HCO^ absorption through different receptor signaling pathways.
机译：高迁移率组盒1（HMGB1）是涉及在败血症和无菌炎性疾病中介导肾功能障碍的损伤相关分子。 HMGB1是响应于感染或损伤的细胞外释放的核蛋白质，其中它与Toll样受体4（TLR4）和其他受体相互作用以介导炎症。以前，我们证明LPS通过基底外侧TLR4-ERK途径（Watts Ba III，George T，Sherwood Er，Good DW，exMirmiol Cell Physiol 301：C1296-C1306 ，2011）。在这里，我们检查了HMGB1是否可以抑制HCO3“通过相同途径的吸收。将HMGB1加入浴中的HCO ^吸收24％在分离的，灌注的大鼠和小鼠MTALS中。与LPS相反，HMGB1的抑制在来自TLR4〜7〜小鼠的MTAL中保存，并且不受ERK抑制剂的影响。通过HMGB1的受体被用于先进的糖化末端产物（RAGE）拮抗剂FPS-ZM1的受体消除抑制，并通过中和抗rage抗体。共聚焦免疫荧光显示出基石外膜结构域的愤怒表达。 HMGB1通过RAGE的HMGB1吸收对HMGB1的吸收抑制作用LPS通过TLR4抑制并通过TLR 2抑制革兰阳性细菌分子。选择性地防止抑制通过Na + / H +交换器1（NHE1）介导的MTAL HCO ^吸收的浴Amiloride，通过HMGB1消除抑制作用。我们得出结论，HMGB1通过从LPS不同于TLR4介导的抑制的侵入依赖性途径抑制MTAL HCOJ吸收。这些研究提供了新的证据，即HMGB1-RAGE信号直接作用损害肾小管的运输功能。它们揭示了脓毒症诱导的肾小管功能障碍的新型范式，由此外源性病原体相关分子和内源性损伤相关分子直接作用，独立地通过不同的受体信号传导途径抑制MTAL HCO ^吸收。

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