Lee Yongwoo, Lee Sang-Hee, Moon Eunyoung, Park Hyerim, Jo Janghyun, Hwang Jung Hwan, Choi Dae Eun
Department of Nephrology, Chungnam National University, Daejeon, Republic of Korea.
Center for Bio-imaging and Translational Research, Korea Basic Science Institute (KBSI), Cheongju, Republic of Korea.
PLoS One. 2025 Sep 8;20(9):e0331582. doi: 10.1371/journal.pone.0331582. eCollection 2025.
Diabetic kidney disease (DKD) involves oxidative stress-driven damage to glomeruli (Gloms) and proximal convoluted tubules (PCT). NAD(P)H: quinone oxidoreductase 1 (NQO1) regulates redox balance, but its compartment-specific role remains unclear. Streptozotocin (STZ)-induced hyperglycemia increased albuminuria and foot process effacement, with NQO1 KO (NKO) mice exhibiting greater podocyte injury than WT, indicating exacerbated glomerular damage. To investigate the underlying mechanisms, we conducted compartment-specific transcriptomic Gene Set Enrichment Analysis (GSEA) in Gloms and PCT. In Gloms, ribosome biogenesis and immune pathways were upregulated in WT-STZ compared to WT but suppressed in NKO-STZ compared to STZ, indicating impaired protein synthesis and immune regulation in NQO1 deficiency. In PCT, ribosome activity, oxidative phosphorylation, glutathione metabolism, and cytoskeletal pathways were elevated in WT-STZ compared to WT but suppressed in NKO-STZ compared to WT-STZ. However, ribosome activity was relatively less affected than in Gloms. Additionally, adherens junction activation was more pronounced in WT-STZ Gloms than in NKO mice Gloms, suggesting a compensatory mechanism to maintain podocyte foot process integrity. This response involved key cytoskeletal genes, including Actg1, Ctnna1, Tjp1, Rhoa, and Iqgap1. These findings highlight compartment-specific adaptive responses to STZ-induced hyperglycemia and underscore NQO1's role in regulating these adaptations. Our results suggest that enhancing NQO1 activity may restore redox balance and preserve nephron integrity, supporting its potential as a therapeutic target for DKD. Furthermore, the observed compartment-specific responses highlight the need for precision redox therapies tailored to glomerular and tubular vulnerabilities.
糖尿病肾病（DKD）涉及氧化应激驱动的肾小球（Gloms）和近端曲管（PCT）损伤。NAD（P）H：醌氧化还原酶1（NQO1）调节氧化还原平衡，但其在特定区域的作用仍不清楚。链脲佐菌素（STZ）诱导的高血糖症增加了蛋白尿和足突消失，NQO1基因敲除（NKO）小鼠表现出比野生型（WT）小鼠更严重的足细胞损伤，表明肾小球损伤加剧。为了研究潜在机制，我们在肾小球和近端曲管中进行了特定区域的转录组基因集富集分析（GSEA）。在肾小球中，与野生型相比，野生型-STZ组的核糖体生物合成和免疫途径上调，但与STZ组相比，NKO-STZ组受到抑制，表明NQO1缺乏时蛋白质合成和免疫调节受损。在近端曲管中，与野生型相比，野生型-STZ组的核糖体活性、氧化磷酸化、谷胱甘肽代谢和细胞骨架途径升高，但与野生型-STZ组相比，NKO-STZ组受到抑制。然而，核糖体活性受到的影响比在肾小球中相对较小。此外，野生型-STZ组肾小球中的黏附连接激活比NKO小鼠肾小球中更明显，提示存在一种维持足细胞足突完整性的代偿机制。这种反应涉及关键的细胞骨架基因，包括Actg1、Ctnna1、Tjp1、Rhoa和Iqgap1。这些发现突出了对STZ诱导高血糖症的特定区域适应性反应，并强调了NQO1在调节这些适应性反应中的作用。我们的结果表明，增强NQO1活性可能恢复氧化还原平衡并维持肾单位完整性，支持其作为DKD治疗靶点的潜力。此外，观察到的特定区域反应突出了针对肾小球和肾小管易损性的精准氧化还原疗法的必要性。
