The proximal tubules play a critical role in phosphate (Pi) homeostasis by reabsorbing Pi via sodium-dependent Pi cotransporters. NPT2A is a major proximal-specific Pi cotransporter, whose expression is regulated by circulating hormones, such as parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23). In this study, we aimed to find a novel regulator in Pi homeostasis.

Using RNA-seq and RT-qPCR analysis, we identified proximal tubule cell–enriched genes. We next used RNAi screening of the identified proximal tubular cell–enriched genes to identify a novel proximal tubule–specific gene that contributes to FGF23- and PTH-mediated inhibition of Pi uptake and NPT2 reduction. We created mice lacking this novel regulator of Pi homeostasis to examine whether the novel regulator contributes to Pi homeostasis in vivo.

We identified 54 kidney-enriched genes, 19 of which are expressed in renal primary proximal tubule cells. One of the proximal tubule–specific genes, TMEM174, interacted with NPT2A, and its knockdown blocked the reduction of NPT2A protein by FGF23 and PTH treatments in human and opossum proximal tubule cells. TMEM174 KO mice had significantly increased levels of serum Pi, FGF23, and PTH, resulting in vascular calcification.

TMEM174 is a novel regulator of Pi homeostasis that interacts with NPT2A.

近端肾小管通过钠依赖性 Pi 协同转运蛋白重吸收 Pi，在磷酸盐 (Pi) 稳态中发挥关键作用。 NPT2A 是一种主要的近端特异性 Pi 协同转运蛋白，其表达受循环激素调节，例如甲状旁腺激素 (PTH) 和成纤维细胞生长因子 23 (FGF23)。在这项研究中，我们的目的是寻找一种新型的 Pi 稳态调节剂。

使用 RNA-seq 和 RT-qPCR 分析，我们鉴定了近端小管细胞富集的基因。接下来，我们对已识别的近端肾小管细胞富集基因进行 RNAi 筛选，以确定一种新的近端肾小管特异性基因，该基因有助于 FGF23 和 PTH 介导的 Pi 摄取抑制和 NPT2 减少。我们创造了缺乏这种新型 Pi 稳态调节剂的小鼠，以检查这种新型调节剂是否有助于体内Pi 稳态。

我们鉴定了 54 个肾脏富集基因，其中 19 个在肾原代近端小管细胞中表达。近端小管特异性基因之一 TMEM174 与 NPT2A 相互作用，其敲低可阻止 FGF23 和 PTH 治疗人类和负鼠近端小管细胞中 NPT2A 蛋白的减少。 TMEM174 KO小鼠血清Pi、FGF23和PTH水平显着升高，导致血管钙化。

TMEM174 是一种新型 Pi 稳态调节剂，可与 NPT2A 相互作用。