Division of Nephrology and Hypertension, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
Division of Pulmonary Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
Am J Physiol Renal Physiol. 2022 Aug 1;323(2):F212-F226. doi: 10.1152/ajprenal.00146.2022. Epub 2022 Jun 27.
Sepsis is a significant cause of mortality in hospitalized patients. Concomitant development of acute kidney injury (AKI) increases sepsis mortality through unclear mechanisms. Although electrolyte disturbances and toxic metabolite buildup during AKI could be important, it is possible that the kidney produces a protective molecule lost during sepsis with AKI. We have previously demonstrated that systemic Tamm-Horsfall protein (THP; uromodulin), a kidney-derived protein with immunomodulatory properties, falls in AKI. Using a mouse sepsis model without severe kidney injury, we showed that the kidney increases circulating THP by enhancing the basolateral release of THP from medullary thick ascending limb cells. In patients with sepsis, changes in circulating THP were positively associated with a critical illness. THP was also found de novo in injured lungs. Genetic ablation of THP in mice led to increased mortality and bacterial burden during sepsis. Consistent with the increased bacterial burden, the presence of THP in vitro and in vivo led macrophages and monocytes to upregulate a transcriptional program promoting cell migration, phagocytosis, and chemotaxis, and treatment of macrophages with purified THP increases phagocytosis. Rescue of septic mice with exogenous systemic THP improved survival. Together, these findings suggest that through releasing THP, the kidney modulates the immune response in sepsis by enhancing mononuclear phagocyte function, and systemic THP has therapeutic potential in sepsis. Specific therapies to improve outcomes in sepsis with kidney injury have been limited by an unclear understanding of how kidney injury increases sepsis mortality. Here, we identified Tamm-Horsfall protein, known to protect in ischemic acute kidney injury, as protective in preclinical sepsis models. Tamm-Horsfall protein also increased in clinical sepsis without severe kidney injury and concentrated in injured organs. Further study could lead to novel sepsis therapeutics.
脓毒症是住院患者死亡的重要原因。急性肾损伤（AKI）的并发发展通过不明机制增加了脓毒症的死亡率。尽管在 AKI 期间电解质紊乱和毒性代谢物的积累可能很重要，但肾脏可能会产生一种在 AKI 合并脓毒症期间丢失的保护性分子。我们之前已经证明，全身性 Tamm-Horsfall 蛋白（THP；尿调蛋白），一种具有免疫调节特性的肾脏来源蛋白，在 AKI 中下降。使用没有严重肾脏损伤的小鼠脓毒症模型，我们表明肾脏通过增强从髓质厚升支细胞基底外侧释放 THP 来增加循环 THP。在脓毒症患者中，循环 THP 的变化与严重疾病呈正相关。THP 也在受损的肺部中首次被发现。在小鼠中敲除 THP 会导致脓毒症期间死亡率和细菌负荷增加。与细菌负荷增加一致，THP 的存在在体外和体内都导致巨噬细胞和单核细胞上调促进细胞迁移、吞噬和趋化的转录程序，并且用纯化的 THP 处理巨噬细胞会增加吞噬作用。用外源性全身性 THP 抢救脓毒症小鼠可提高存活率。总之，这些发现表明，肾脏通过增强单核吞噬细胞功能来调节脓毒症中的免疫反应，而全身性 THP 在脓毒症中具有治疗潜力。由于不清楚肾脏损伤如何增加脓毒症的死亡率，因此改善伴有肾脏损伤的脓毒症结局的特定疗法受到限制。在这里，我们确定了 Tamm-Horsfall 蛋白（已知可在缺血性急性肾损伤中起保护作用）作为临床前脓毒症模型中的保护性蛋白。Tamm-Horsfall 蛋白在没有严重肾脏损伤的临床脓毒症中也增加，并集中在受损器官中。进一步的研究可能会导致新的脓毒症治疗方法。
