Elucidating function and signaling of Gpr126 in kidney development and disease

急性肾损伤和慢性肾脏疾病（CKD）共同代表了世界范围内增长最快的病理。CKD的患病率在许多国家为10%左右。由于目前还没有有效的治疗方法来恢复肾脏功能，因此建立诊断标记物/治疗方法来预防、减少甚至逆转肾脏损害是很重要的。粘附G蛋白偶联受体（agpcr）是GPCR超家族的第二大类别，但对其了解甚少。gpcr与许多人类疾病有关，目前在美国食品和药物管理局批准的所有药物中，约34%的药物都以gpcr为靶点。因此，揭示未被充分研究的gpcr的功能提供了大量未开发的治疗潜力。我们的初步数据表明，aGPCR Gpr126在斑马鱼、小鼠、大鼠和人的肾脏中表达，并在发育过程中在上皮细胞中富集。在成人肾脏中，Gpr126在肾小球旁细胞、壁上皮细胞（PECs）、集管上皮细胞和尿路上皮中表达。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，输尿管芽正常分支需要Gpr126。此外，对两个斑马鱼突变体的分析表明，gpr126是管状形态形成和管状片段规范所必需的。最后，分析Gpr126在动物模型和患者损伤/病变肾脏中的表达变化表明，Gpr126在收集管上皮细胞和/或PECs中显著上调。基于这些数据，我们假设i) Gpr126有助于肾元的分化，建立节段同一性。ii) Gpr126可作为肾脏疾病的诊断标志物。iii) Gpr126是一个有前景的肾脏疾病治疗新靶点。在这里，我们建议通过以下方法来验证这些假设：1)鉴定由Gpr126控制的肾脏发育和疾病的细胞过程。2)确定体内Gpr126的相互作用伙伴。3)分析肾特异性Gpr126 KO小鼠和斑马鱼Gpr126突变体。4)确定可诱导肾特异性Gpr126 KO在肾脏疾病中的作用。考虑到aGPCR是GPCR超家族的第二大类别，但人们对其了解甚少，而且Gpr126迄今尚未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是肾脏学领域的重大兴趣，也是aGPCR领域和考虑肾脏疾病社会经济负担的公众的重大兴趣。

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.