Department II of Internal Medicine, University Hospital Cologne, Faculty of Medicine, University of Cologne, 50937 Cologne, Germany.
Center for Molecular Medicine Cologne, University Hospital Cologne, Faculty of Medicine, University of Cologne, 50931 Cologne, Germany.
Cells. 2023 Jan 10;12(2):271. doi: 10.3390/cells12020271.
Reactive oxygen species (ROS), which excessively arise in diabetes and systemic inflammatory diseases, modify cellular lipids and cellular lipid composition leading to altered biophysical properties of cellular membranes. The impact of lipid peroxidation on transmembrane signaling routes is not yet well studied. The canonical transient receptor potential channel 6 (TRPC6) is implicated in the pathogenesis of several forms of glomerular diseases. TRPC6 is sensitive to membrane stretch and relies on a distinct lipid environment. This study investigates the effect of oxidative alterations to plasma membrane lipids on TRPC6 activity and the function of the glomerular filter. Knockout of the anti-oxidative, lipid modifying enzyme paraoxonase 2 (PON2) leads to altered biophysical properties of glomerular epithelial cells, which are called podocytes. Cortical stiffness, quantified by atomic force microscopy, was largely increased in PON2-deficient cultured podocytes. PON2 deficiency markedly enhanced TRPC6 channel currents and channel recovery. Treatment with the amphiphilic substance capsazepine in micromolar doses reduced cortical stiffness and abrogated TRPC6 conductance. In in vivo studies, capsazepine reduced the glomerular phenotype in the model of adriamycin-induced nephropathy in PON2 knockout mice and wildtype littermates. In diabetic AKITA mice, the progression of albuminuria and diabetic kidney disease was delayed. In summary, we provide evidence that the modification of membrane characteristics affects TRPC6 signaling. These results could spur future research to investigate modification of the direct lipid environment of TRPC6 as a future therapeutic strategy in glomerular disease.
活性氧（ROS）在糖尿病和全身性炎症性疾病中过度产生，修饰细胞脂质和细胞脂质组成，导致细胞膜的生物物理性质发生改变。脂质过氧化对跨膜信号转导途径的影响尚未得到很好的研究。经典瞬时受体电位通道 6（TRPC6）参与多种形式的肾小球疾病的发病机制。TRPC6对细胞膜拉伸敏感，并依赖于独特的脂质环境。本研究探讨了质膜脂质的氧化改变对 TRPC6 活性和肾小球滤过功能的影响。抗氧化、脂质修饰酶对氧磷酶 2（PON2）的敲除导致肾小球上皮细胞（称为足细胞）的生物物理特性发生改变。通过原子力显微镜定量的皮质硬度在 PON2 缺陷培养的足细胞中大大增加。PON2 缺乏显著增强了 TRPC6 通道电流和通道恢复。用亲脂性物质辣椒素以微摩尔剂量处理可降低皮质硬度并阻断 TRPC6 电导。在体内研究中，辣椒素在 PON2 敲除小鼠和野生型同窝仔鼠的阿霉素诱导的肾病模型中减轻了肾小球表型。在糖尿病 AKITA 小鼠中，白蛋白尿和糖尿病肾病的进展得到延缓。总之，我们提供了证据表明，膜特性的改变会影响 TRPC6 信号。这些结果可能会促使未来的研究探索作为肾小球疾病的未来治疗策略，直接改变 TRPC6 的脂质环境。
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