Department of Cell Biology, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Pharmacological Study Group, Pharmaceutical Research Laboratories, Sanwa Kagaku Kenkyusho, Mie, Japan.
Nefrologia (Engl Ed). 2021 Sep-Oct;41(5):539-547. doi: 10.1016/j.nefroe.2021.11.007.
Topiroxostat, an inhibitor of xanthine oxidoreductase (XOR) was shown to reduce urinary albumin excretion of hyperuricemic patients with chronic kidney disease. However, its pharmacological mechanism is not well understood. In this study, we examined the effects of topiroxostat on glomerular podocytes. Podocyte is characterized by foot process and a unique cell-cell junction slit diaphragm functioning as a final barrier to prevent proteinuria.
The effects of topiroxostat on the expressions of podocyte functional molecules were analysed in db/db mice, a diabetic nephropathy model, anti-nephrin antibody-induced rat podocyte injury model and cultured podocytes treated with adriamycin.
Topiroxostat treatment ameliorated albuminuria in db/db mice. The expression of desmin, a podocyte injury marker was increased, and nephrin and podocin, key molecules of slit diaphragm, and podoplanin, an essential molecule in maintaining foot process were downregulated in db/db mice. Topiroxostat treatment prevented the alterations in the expressions of these molecules in db/db mice. XOR activity in kidney was increased in rats with anti-nephrin antibody-induced podocyte injury. Topiroxostat treatment reduced XOR activity and restored the decreased expression of nephrin, podocin and podoplanin in the podocyte injury. Furthermore, topiroxostat enhanced the expression of podoplanin in injured human cultured podocytes.
Podocyte injury was evident in db/db mice. Topiroxostat ameliorated albuminuria in diabetic nephropathy model by preventing podocyte injury. Increase of XOR activity in kidney contributes to development of podocyte injury caused by stimulation to slit diaphragm. Topiroxostat has an effect to stabilize slit diaphragm and foot processes by inhibiting the reduction of nephrin, podocin and podoplanin.
黄嘌呤氧化酶（XOR）抑制剂托匹司他可降低合并慢性肾脏病的高尿酸血症患者的尿白蛋白排泄量。然而，其药理机制尚不清楚。本研究旨在探讨托匹司他对肾小球足细胞的影响。足细胞的特征是足突和独特的细胞-细胞连接裂孔隔膜，作为阻止蛋白尿的最终屏障。
在糖尿病肾病模型 db/db 小鼠、抗肾素抗体诱导的大鼠足细胞损伤模型和用阿霉素处理的培养足细胞中，分析托匹司他对足细胞功能分子表达的影响。
托匹司他治疗可改善 db/db 小鼠的白蛋白尿。db/db 小鼠的足突损伤标志物-desmin 表达增加，裂孔隔膜关键分子-nephrin 和 podocin 以及维持足突的必需分子-podoplanin 表达下调。托匹司他治疗可预防 db/db 小鼠这些分子表达的改变。抗肾素抗体诱导的足细胞损伤大鼠肾脏 XOR 活性增加。托匹司他治疗可降低 XOR 活性，恢复足细胞损伤中 nephrin、podocin 和 podoplanin 的表达减少。此外，托匹司他可增强受损人源培养足细胞中 podoplanin 的表达。
db/db 小鼠足细胞损伤明显。托匹司他通过预防足细胞损伤改善糖尿病肾病模型的白蛋白尿。肾脏 XOR 活性的增加导致刺激裂孔隔膜引起的足细胞损伤。托匹司他通过抑制 nephrin、podocin 和 podoplanin 的减少，对稳定裂孔隔膜和足突具有作用。
