Elucidating function and signaling of Gpr126 in kidney development and disease

急性肾脏损伤和慢性肾脏疾病(CKD)共同代表着全球增长最快的病理。慢性肾脏病在许多国家的患病率为10%。由于目前还没有有效的治疗方法来恢复肾功能，因此建立预防、减少甚至逆转肾损害的诊断标志物/治疗方法是很重要的。黏附G蛋白偶联受体(AGPCRs)是GPCR超家族中第二大类，但人们对它们知之甚少。GPCRs涉及许多人类疾病，目前约34%的美国食品和药物管理局批准的药物是GPCRs的靶标。因此，揭示未被研究的GPCRs的功能提供了丰富的未开发的治疗潜力。我们的初步数据显示，aGPCRGPR126在斑马鱼、小鼠、大鼠和人类的肾脏中表达，并在发育过程中在上皮细胞中变得丰富。在成人肾脏中，GPR126表达于肾小球旁细胞、壁上皮细胞、集合管上皮细胞以及尿路上皮细胞。此外，利用外植体培养对GPR126基因敲除小鼠的肾脏进行分析表明，GPR126是正常的输尿管芽分支所必需的。此外，对两个斑马鱼突变体的分析表明，GPR126在管状形态发生和管节的指定中是必需的。最后，对GPR126在动物模型和患者损伤/病变肾脏中表达变化的分析表明，GPR126在收集导管上皮细胞和/或PECs时显著上调。基于这些数据，我们假设：1)GPR126有助于肾单位的分化，建立节段同一性。2)GPR126可作为肾脏疾病的诊断标记物。3)GPR126是治疗肾脏疾病的一个很有前途的新靶点。在这里，我们建议通过1)确定GPR126在肾脏发育和疾病中控制的细胞过程来检验这些假说。2)确定体内GPR126相互作用伙伴。3)对肾脏特异的GPR126 KO小鼠和斑马鱼GPR126突变体进行分析。4)检测诱导性肾脏特异性GPR126KO在肾脏疾病中的作用。鉴于aGPCRs是GPCR超家族中的第二大类，但人们对其知之甚少，而且GPR126到目前为止还没有在肾脏发育和疾病的背景下进行研究，阐明GPR126在肾脏发育和疾病中的作用不仅引起了肾病学领域的极大兴趣，也引起了aGPCR界和普通公众的极大兴趣，因为肾脏疾病造成了社会经济负担。

Acute kidney injury and chronic kidney disease (CKD) represent together the fastest-growing pathology worldwide. The prevalence of CKD is in many countries > 10%. As currently no effective therapies exist to restore kidney function, it is important to establish diagnostic markers/therapies that prevent, reduce, or even reverse kidney damage. Adhesion G protein-coupled receptors (aGPCRs) represent the second largest class of the GPCR superfamily, but they are poorly understood. GPCRs are involved in many human diseases and are currently targeted by ~34% of all approved drugs by the US Food and Drug Administration. Therefore, uncovering the function of understudied GPCRs provides a wealth of untapped therapeutic potential. Our preliminary data show that the aGPCR Gpr126 is expressed in zebrafish, mice, rats, and humans in the kidney and becomes enriched in epithelial cells during development. In the adult kidney, Gpr126 is expressed in juxtaglomerular cells, parietal epithelial cells (PECs), and the collecting duct epithelial cells, as well as the urothelium. In addition, analysis of the kidneys of Gpr126 knockout mice utilizing explant cultures shows that Gpr126 is required for proper ureteric bud branching. Furthermore, the analysis of two zebrafish mutants revealed that gpr126 is required for tubular morphogenesis and specification of tubular segments. Finally, the analysis of Gpr126 expression changes in injured/diseased kidneys from animal models as well as patients shows that Gpr126 is markedly upregulated in collecting duct epithelial cells and/or PECs. Based on these data we hypothesize that i) Gpr126 contributes to the differentiation of the nephron establishing segment identity. ii) Gpr126 is useful as a diagnostic marker in kidney disease. iii) Gpr126 is a promising new therapeutic target for renal diseases. Here, we propose to test these hypotheses by 1) Identifying cellular processes controlled by Gpr126 in kidney development and disease. 2) Determining the in vivo Gpr126 interaction partners. 3) Analyzing kidney-specific Gpr126 KO mice and zebrafish gpr126 mutants. 4) Determining the effect of inducible kidney-specific Gpr126 KO in kidney disease. Considering that aGPCRs represent the second largest class of the GPCR superfamily but are poorly understood and that Gpr126 has so far neither been studied in the context of kidney development nor disease, elucidating the role of Gpr126 in kidney development and disease is not only of great interest to the field of nephrology but also the aGPCR field and the general public considering the socioeconomic burden of kidney disease.