Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294-0007, USA.
Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294-0007, USA; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, 35294-0007, USA; Department of Veterans Affairs Medical Center, Birmingham, AL, 35233, USA.
Free Radic Biol Med. 2021 Aug 1;171:80-90. doi: 10.1016/j.freeradbiomed.2021.05.011. Epub 2021 May 12.
A major cause of morbidity and mortality in multiple myeloma is kidney injury from overproduction of monoclonal immunoglobulin light chains (FLC). FLC can induce damage through the production of hydrogen peroxide, which activates pro-inflammatory and pro-apoptotic pathways. The present study focused on catalase, a highly conserved antioxidant enzyme that degrades hydrogen peroxide. Initial findings were that FLC increased hydrogen peroxide levels but also decreased catalase levels and activity in proximal tubule epithelium. In order to clarify, we showed that the phosphatidylinositol 3-kinase inhibitor, LY294002, inhibited FLC-induced Akt-mediated deactivation of Forkhead box O class 3a (FoxO3a) and increased catalase activity in proximal tubule cells. Augmented catalase activity decreased FLC-mediated production of hydrogen peroxide as well as the associated increase in High Mobility Group Box 1 (HMGB1) protein release and caspase-3 activity. Coincubation of cells with FLC and an allosteric activator of Sirtuin 1 (SIRT1) was also sufficient to increase catalase activity and promote similar cytoprotective effects. Our studies confirmed that the mechanism of downregulation of catalase by FLC involved deactivation of FoxO3a and inhibition of SIRT1. Mechanistic understanding of catalase regulation allows for future treatments that target pathways that increase catalase in the setting of proximal tubule injury from FLC.
在多发性骨髓瘤中，发病率和死亡率的一个主要原因是单克隆免疫球蛋白轻链（FLC）过度产生导致的肾脏损伤。FLC 可以通过产生过氧化氢来诱导损伤，从而激活促炎和促凋亡途径。本研究集中于过氧化氢酶，一种高度保守的抗氧化酶，可降解过氧化氢。最初的发现是 FLC 增加了过氧化氢的水平，但也降低了近端肾小管上皮细胞中的过氧化氢酶水平和活性。为了澄清这一点，我们表明，磷脂酰肌醇 3-激酶抑制剂 LY294002 抑制了 FLC 诱导的 Akt 介导的 Forkhead box O 类 3a（FoxO3a）失活，并增加了近端肾小管细胞中的过氧化氢酶活性。增强的过氧化氢酶活性降低了 FLC 介导的过氧化氢产生，以及相关的高迁移率族蛋白 1（HMGB1）蛋白释放和半胱天冬酶-3 活性的增加。细胞与 FLC 和 Sirtuin 1（SIRT1）的别构激活剂共同孵育也足以增加过氧化氢酶活性并促进类似的细胞保护作用。我们的研究证实，FLC 下调过氧化氢酶的机制涉及 FoxO3a 的失活和 SIRT1 的抑制。对过氧化氢酶调节机制的理解为将来的治疗提供了可能，即在 FLC 引起的近端肾小管损伤中靶向增加过氧化氢酶的途径。
