SMPDL3b in Podocytes: Decoupling Proteinuria from CKD Progression in Experimental Alport Syndrome

Alport Syndrome (AS) is a rare genetic disease with impaired production of collagen type IV alpha 3, 4 and 5 chains in the glomerular basement membranes (GBM), which results amongst others in progressive loss of kidney function. In AS, abnormalities in the GBM and associated podocyte detachment may potentially result from the dysregulation of sphingolipid metabolism. Here we investigated whether renal sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) overexpression modulates the generation of sphingosine-1-phosphate (S1P) and contributes to renal failure in Col4a3 knockout mice, a mouse model of AS. We found a 3-fold increase in SMPDL3b expression in glomeruli and murine podocytes isolated from Col4a3 knockout mice. Increased SMPDL3b expression occurred in association with increased glomerular S1P levels, while podocyte specific Smpdl3b deletion in Col4a3 knockout mice was sufficient to restore S1P levels and to reduce proteinuria and podocyte foot process but not sufficient to protect from renal failure. Thus, podocyte S1P may be a key modulator of proteinuria and podocyte integrity in AS. Our study in experimental AS suggests that SMPDL3b-derived S1P may dissociate proteinuria from renal failure, and suggests that improvement of glomerular structure and function may not always translate in protection from CKD progression in AS.

奥尔波特综合征（Alport Syndrome, AS）是一种罕见的遗传性疾病，患者肾小球基底膜（glomerular basement membranes, GBM）中IV型胶原蛋白α3、α4及α5链的合成受损，进而引发包括肾功能进行性减退在内的多种病理表现。在奥尔波特综合征中，肾小球基底膜异常及伴随的足细胞脱落，可能由鞘脂代谢紊乱诱发。本研究旨在探讨肾脏酸性鞘磷脂磷酸二酯酶样3b（sphingomyelin phosphodiesterase acid-like 3b, SMPDL3b）的过表达是否可调控1-磷酸鞘氨醇（sphingosine-1-phosphate, S1P）的生成，并在Col4a3基因敲除小鼠（一种奥尔波特综合征小鼠模型）中参与肾衰竭的发生发展。我们在从Col4a3基因敲除小鼠中分离得到的肾小球及小鼠足细胞内，检测到SMPDL3b的表达水平上调3倍。SMPDL3b表达升高与肾小球内S1P水平增加显著相关；而在Col4a3基因敲除小鼠中特异性敲除足细胞Smpdl3b，足以恢复S1P水平并减轻蛋白尿及足细胞足突异常，但无法阻止肾衰竭的进展。由此可见，足细胞来源的S1P或许是奥尔波特综合征中蛋白尿发生与足细胞完整性维持的关键调控因子。本实验性奥尔波特综合征研究表明，SMPDL3b介导生成的S1P可能将蛋白尿与肾衰竭的病理进程分离开来，同时提示肾小球结构与功能的改善，并不总能转化为对奥尔波特综合征患者慢性肾脏病（chronic kidney disease, CKD）进展的保护效应。