Phosphatidylserine (PS) is asymmetrically concentrated in the cytoplasmic leaflet of eukaryotic cell plasma membranes. This asymmetry is regulated by a group of P4 ATPases (named PS flippases) and its β-subunit TMEM30A. The disruption of PS flippase leads to severe human diseases. Tmem30a is essential in the mouse retina, cerebellum and liver. However, the role of Tmem30a in the kidney, where it is highly expressed, remains unclear. Podocytes in the glomerulus form a branched interdigitating filtration barrier that can prevent the traversing of large cellular elements and macromolecules from the blood into the urinary space. Damage to podocytes can disrupt the filtration barrier and lead to proteinuria and podocytopathy, including focal segmental glomerulosclerosis, minimal change disease, membranous nephropathy, and diabetic nephropathy. To investigate the role of Tmem30a in the kidney, we generated a podocyte-specific Tmem30a knockout (cKO) mouse model using the NPHS2-Cre line. Tmem30a KO mice displayed albuminuria, podocyte degeneration, mesangial cell proliferation with prominent extracellular matrix accumulation and eventual progression to focal segmental glomerulosclerosis (FSGS). Reduced TMEM30A expression was observed in patients with minimal change disease and membranous nephropathy, highlighting the clinical importance of TMEM30A in podocytopathy. Our data demonstrate a critical role of Tmem30a in maintaining podocyte survival and glomerular filtration barrier integrity. Understanding the dynamic regulation of the PS distribution in the glomerulus provides a unique perspective to pinpoint the mechanism of podocyte damage and potential therapeutic targets.

中文翻译：

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足细胞中磷脂酰丝氨酸翻转酶β亚基Tmem30a的丢失导致白蛋白尿和肾小球硬化

磷脂酰丝氨酸（PS）不对称地集中在真核细胞质膜的细胞质小叶中。这种不对称性由一组P4 ATPase（称为PS flippases）及其β亚基TMEM30A调节。PS翻转酶的破坏导致严重的人类疾病。Tmem30a在小鼠视网膜，小脑和肝脏中必不可少。但是，尚不清楚Tmem30a在高表达的肾脏中的作用。肾小球中的足细胞形成分支的相互交叉的过滤屏障，可以阻止大的细胞成分和大分子从血液进入尿液空间。对足细胞的损害会破坏滤过屏障并导致蛋白尿和足病，包括局灶性节段性肾小球硬化，微小改变疾病，膜性肾病和糖尿病性肾病。为了研究Tmem30a在肾脏中的作用，我们使用NPHS2-Cre细胞系生成了足细胞特异性Tmem30a敲除（cKO）小鼠模型。Tmem30a KO小鼠表现出白蛋白尿，足细胞变性，肾小球膜细胞增生，并伴有明显的细胞外基质积聚，最终发展为局灶性节段性肾小球硬化（FSGS）。在具有最小变化疾病和膜性肾病的患者中观察到TMEM30A表达降低，这突出了TMEM30A在足底病中的临床重要性。我们的数据证明了Tmem30a在维持足细胞存活和肾小球滤过屏障完整性方面的关键作用。了解肾小球PS分布的动态调节提供了一个独特的观点，可以查明足细胞损伤的机制和潜在的治疗靶点。