足细胞中的SMPDL3b酶在实验性奥尔波特综合征中使蛋白尿与慢性肾病进展脱钩。
The enzyme SMPDL3b in podocytes decouples proteinuria from chronic kidney disease progression in experimental Alport Syndrome.
作者信息
Mitrofanova Alla, Fontanella Antonio M, Molina Judith, Zhang Guanshi, Mallela Shamroop K, Severino Luisa Ulloa, Santos J Javier Varona, Tolerico Matthew, Njeim Rachel, Issa Wadih, Boulina Maria, Carrazco Arianna, Semenova Veronika, Zuo Yiqin, Ficarella Maria, Kim Jin Ju, Sloan Alexis, Sharma Kumar, Yuen Darren A, Perin Laura, Burke George W, Fornoni Alessia, Merscher Sandra
机构信息
Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, Florida, USA.
Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, Florida, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, Florida, USA.
出版信息
Kidney Int. 2025 Aug;108(2):253-270. doi: 10.1016/j.kint.2025.04.024. Epub 2025 May 30.
BACKGROUND
Chronic kidney disease, including Alport Syndrome, is linked to collagen type IV mutations, lipid dysmetabolism, and altered sphingolipid pathways, with no targeted therapies currently available. Sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b), a key regulator of sphingolipid metabolism and membrane receptor organization in podocytes, may drive disease via ceramide and sphingosine-1-phosphate pathways. This study tested whether altered SMPDL3b expression contributes to glomerular injury and renal decline in Alport Syndrome.
METHODS
Archived Alport Syndrome human biopsies were used for immunohistochemistry and NanoString re-analysis of SMPDL3b. Murine podocytes isolated from mouse models of Alport Syndrome were profiled using Illumina. Mouse models of Alport Syndrome and models with either podocyte-specific deletion or inducible overexpression of Smpdl3b were generated to assess renal function using liquid chromatography-mass spectrometry, matrix-assisted laser desorption ionization-mass spectrometry imaging and atomic force microscopy.
RESULTS
We found a three-fold increase in SMPDL3b expression in glomeruli, tubules and murine podocytes isolated from Col4a3 knockout mice. Increased SMPDL3b expression occurred in association with alterations affecting kidney sphingolipid metabolism, increased glomerular but not tubular sphingosine-1-phosphate levels and reduced glomerular basement membrane and podocyte stiffness. Podocyte-specific Smpdl3b deletion in Col4a3 knockout mice was sufficient to restore sphingosine-1-phosphate levels, to reduce proteinuria, podocyte foot process effacement, and improve glomerular basement membrane and podocyte stiffness, but not sufficient to protect from kidney failure.
CONCLUSIONS
Our study suggests that SMPDL3b may be a key modulator of proteinuria and podocyte integrity in Alport Syndrome, decoupling proteinuria from kidney failure, and suggests that improvement of glomerular structure and function may not always translate into protection from chronic kidney disease progression.
背景
慢性肾脏病，包括阿尔波特综合征，与IV型胶原突变、脂质代谢紊乱和鞘脂途径改变有关，目前尚无针对性治疗方法。鞘磷脂磷酸二酯酶酸性样3b（SMPDL3b）是足细胞中鞘脂代谢和膜受体组织的关键调节因子，可能通过神经酰胺和1-磷酸鞘氨醇途径引发疾病。本研究测试了SMPDL3b表达改变是否导致阿尔波特综合征中的肾小球损伤和肾功能下降。
方法
使用存档的阿尔波特综合征人类活检组织进行SMPDL3b的免疫组织化学和NanoString再分析。使用Illumina对从阿尔波特综合征小鼠模型中分离的小鼠足细胞进行分析。构建阿尔波特综合征小鼠模型以及足细胞特异性缺失或诱导性过表达Smpdl3b的模型，使用液相色谱-质谱、基质辅助激光解吸电离-质谱成像和原子力显微镜评估肾功能。
结果
我们发现从Col4a3基因敲除小鼠分离的肾小球、肾小管和小鼠足细胞中SMPDL3b表达增加了三倍。SMPDL3b表达增加与影响肾脏鞘脂代谢的改变、肾小球而非肾小管中1-磷酸鞘氨醇水平升高以及肾小球基底膜和足细胞硬度降低有关。在Col4a3基因敲除小鼠中特异性删除足细胞中的Smpdl3b足以恢复1-磷酸鞘氨醇水平，减少蛋白尿、足细胞足突消失，并改善肾小球基底膜和足细胞硬度，但不足以预防肾衰竭。
结论
我们的研究表明，SMPDL3b可能是阿尔波特综合征中蛋白尿和足细胞完整性的关键调节因子，使蛋白尿与肾衰竭脱钩，并表明肾小球结构和功能的改善不一定能转化为对慢性肾脏病进展的预防。
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