Abstract：
Chronic kidney disease (CKD) is associated with renal lipid dysmetabolism among a variety of other pathways. We recently demonstrated that oxysterol-binding protein like 7 (OSBPL7) modulates the expression and function of ATP Binding Cassette Subfamily A Member 1 (ABCA1) in podocytes, a specialized type of cell essential for kidney filtration. Drugs that target OSBPL7 lead to improved renal outcomes in several experimental models of CKD. However, the role of OSBPL7 in podocyte injury remains unclear. Employing mouse models and cellular assays, we investigated the influence of OSBPL7 deficiency on podocytes. We demonstrated that reduced renal OSBPL7 levels as observed in two different models of experimental CKD are linked to increased podocyte apoptosis, primarily mediated by heightened endoplasmic reticulum (ER) stress. While as expected the absence of OSBPL7 also resulted in lipid dysregulation (increased lipid droplets and triglycerides content), OSBPL7-deficiency related lipid dysmetabolism did not contribute to podocyte injury. Similarly, we demonstrated that the decreased autophagic flux we observed in OSBPL7-deficient podocytes was not the mechanistic link between OSBPL7-deficiency and apoptosis. In a complementary zebrafish model, osbpl7 knockdown was sufficient to induce proteinuria and morphological damage to the glomerulus, underscoring its physiological relevance. Our study shed new light on the mechanistic link between OSBPL7 deficiency and podocyte injury in glomerular diseases associated with CKD, and it strengthen the role of OSBPL7 as a novel therapeutic target.
摘要：
慢性肾脏病（CKD）与多种其他途径中的肾脏脂质代谢异常有关。我们最近证明了氧固醇结合蛋白7（OSBPL7）调节足细胞中ATP结合盒亚家族A成员1（ABCA1）的表达和功能，肾脏过滤所必需的一种特殊类型的细胞。靶向OSBPL7的药物在几个CKD实验模型中导致改善的肾脏结果。然而,OSBPL7在足细胞损伤中的作用尚不清楚.采用小鼠模型和细胞分析，我们调查了OSBPL7缺乏对足细胞的影响。我们证明，在两种不同的实验性CKD模型中观察到的肾脏OSBPL7水平降低与足细胞凋亡增加有关。主要由增强的内质网（ER）应激介导。正如预期的那样，OSBPL7的缺失也会导致脂质失调（脂质滴和甘油三酯含量增加）。OSBPL7缺乏相关的脂质代谢异常不会导致足细胞损伤。同样，我们证明,我们在OSBPL7缺陷足细胞中观察到的自噬通量降低不是OSBPL7缺陷与细胞凋亡之间的机制联系.在互补斑马鱼模型中，osbpl7敲低足以诱导蛋白尿和肾小球形态损伤，强调其生理相关性。我们的研究揭示了与CKD相关的肾小球疾病中OSBPL7缺乏和足细胞损伤之间的机制联系。它加强了OSBPL7作为新的治疗靶点的作用。
