Baranovskaya Irina, Volk Kevin, Alexander Sati, Abais-Battad Justine, Mamenko Mykola
Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, United States.
Front Physiol. 2024 Aug 14;15:1399396. doi: 10.3389/fphys.2024.1399396. eCollection 2024.
Lithium (Li) therapy is a valuable tool in psychiatric practice that remains underutilized due to safety concerns. Excessive plasma Li levels are nephrotoxic and can trigger a local immune response. Our understanding of the immunomodulatory effects of Li in the kidney is fragmentary. Here, we studied how immune mechanisms contribute to the development of Li-induced adverse effects in the kidneys of C57BL/6NJ mice placed on a 0.3% lithium carbonate diet for 28 days. We combined histochemical techniques, immunoblotting, flow cytometry, qPCR and proteome profiler arrays to characterize renal tissue damage, infiltrating immune cells and cytokine markers, activation of pyroptotic and apoptotic cascades in the kidneys of mice receiving Li-containing and regular diets. We found that biomarkers of tubular damage, kidney injury marker, KIM-1, and neutrophil gelatinase-associated lipocalin, NGAL, were elevated in the renal tissue of Li-treated mice when compared to controls. This correlated with increased interstitial fibrosis in Li-treated mice. Administration of Li did not activate the pro-inflammatory NLRP3 inflammasome cascade but promoted apoptosis in the renal tissue. The TUNEL-positive signal and levels of pro-apoptotic proteins, Bax, cleaved caspase-3, and caspase-8, were elevated in the kidneys of Li-treated mice. We observed a significantly higher abundance of CD93, CCL21, and fractalkine, accumulation of F4.80 macrophages with reduced M1/M2 polarization ratio and decreased CD4 levels in the renal tissue of Li-treated mice when compared to controls. Therefore, after 28 days of treatment, Li-induced insult to the kidney manifests in facilitated apoptotic cell death without an evident pro-inflammatory response.
锂（Li）疗法是精神科实践中的一种重要工具，但由于安全问题其应用仍未得到充分利用。血浆锂水平过高具有肾毒性，可引发局部免疫反应。我们对锂在肾脏中的免疫调节作用的了解尚不完整。在此，我们研究了免疫机制如何在给予0.3%碳酸锂饮食28天的C57BL/6NJ小鼠肾脏中导致锂诱导的不良反应。我们结合组织化学技术、免疫印迹、流式细胞术、qPCR和蛋白质组分析阵列，以表征接受含锂饮食和常规饮食的小鼠肾脏中的组织损伤、浸润免疫细胞和细胞因子标志物、焦亡和凋亡级联反应的激活情况。我们发现，与对照组相比，接受锂治疗的小鼠肾组织中肾小管损伤的生物标志物、肾损伤标志物KIM-1和中性粒细胞明胶酶相关脂质运载蛋白NGAL升高。这与接受锂治疗的小鼠间质纤维化增加相关。给予锂并未激活促炎性NLRP3炎性小体级联反应，但促进了肾组织中的细胞凋亡。接受锂治疗的小鼠肾脏中TUNEL阳性信号以及促凋亡蛋白Bax、裂解的caspase-3和caspase-8的水平升高。与对照组相比，我们观察到接受锂治疗的小鼠肾组织中CD93、CCL21和趋化因子的丰度显著更高，F4/80巨噬细胞积累，M1/M2极化率降低，CD4水平降低。因此，治疗28天后，锂诱导的肾损伤表现为凋亡性细胞死亡加速，而无明显的促炎反应。
