The renal serotonin-system: a new target for the inhibition of renal disease progression

肾脏血清素系统：抑制肾脏疾病进展的新靶点

• 批准号: 299183141
• 负责人: Professor Dr. Tammo Ostendorf
• 金额: --
• 依托单位: Klinik für Nieren- und Hochdruckkrankheiten, Rheumatologische und Immunologische Erkrankungen (Medizinische Klinik II)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/299183141?language=en
• 关键词: renal; serotonin; system; new; target

Besides inhibitors of the renin-angiotensin system, presently only few specific treatment options exist, which inhibit the loss of functional nephrons during progressive renal diseases as well as the development of kidney fibrosis. Given the increasing numbers of patients with acute or chronic renal failure, which meanwhile has reached pandemic dimensions, the identification of new treatment targets is urgently needed. In this context the serotonin-receptors 5-HTR-2a and/or -2b are of great interest, since their pro-fibrotic role is well-documented in several organs like skin, lung and liver, and since pharmacological options to intervene already exist. More importantly, it has been shown that blockade of the receptors can even reverse established fibrosis. This has hardly ever been documented in the kidney, but would be of major clinical interest. Concerning the role of the renal serotonin-system in acute and chronic renal disease virtually no data exist. In extensive pilot studies, we obtained data suggesting a pro-fibrotic role of 5-HTR-2a and -2b in the kidney, but also suggesting functions in the regeneration of tubular cells. In detail, these functions in the kidney obviously differ from those in other organs. In the present study, we want to test the hypothesis that 5-HTR-2a and -2b receptors are important mediators of acute and chronic renal damage, and that in vivo neutralization of one or both receptors represents a new therapeutic approach in kidney diseases. The hypothesis will be tested in four experimental approaches: 1) Expression-analyses of 5-HTR-2a and -2b in human and experimental renal diseases, 2) in vitro-analyses on the role of 5-HTR-2a and -2b in glomerular parietal and renal tubular cells, followed by 3) studies on the pathophysiological role of 5-HTR-2a und -2b in acute and chronic kidney damage. Finally 4) an in vivo neutralization of 5-HTR-2a and/or -2b will be performed in early disease as well as in established renal fibrosis.

除了肾素-血管紧张素系统的抑制剂之外，目前仅存在很少的特异性治疗选择，其抑制进行性肾病期间功能性肾单位的损失以及肾纤维化的发展。鉴于急性或慢性肾衰竭患者数量不断增加，同时已达到大流行的程度，迫切需要确定新的治疗目标。在这种情况下，胡萝卜素受体5-HTR-2a和/或-2b是非常令人感兴趣的，因为它们的促纤维化作用在几个器官如皮肤、肺和肝中有充分的记载，并且因为已经存在干预的药理学选择。更重要的是，已经表明受体的阻断甚至可以逆转已建立的纤维化。这在肾脏中几乎从未有过记录，但将具有重大的临床意义。关于肾脏降钙素系统在急性和慢性肾脏疾病中的作用，几乎没有数据存在。在广泛的初步研究中，我们获得的数据表明5-HTR-2a和-2b在肾脏中的促纤维化作用，但也表明在肾小管细胞再生中的功能。具体而言，肾脏的这些功能明显不同于其他器官。在本研究中，我们想测试的假设，5-HTR-2a和-2b受体是急性和慢性肾损伤的重要介质，在体内中和一个或两个受体代表了一种新的治疗方法在肾脏疾病。该假设将在四种实验方法中进行检验：1）5-HTR-2a和-2b在人类和实验性肾脏疾病中的表达分析，2）5-HTR-2a和-2b在肾小球壁细胞和肾小管细胞中的作用的体外分析，随后3）5-HTR-2a和-2b在急性和慢性肾损伤中的病理生理学作用的研究。最后，4）在早期疾病以及已建立的肾纤维化中进行5-HTR-2a和/或-2b的体内中和。

项目成果

Identification of platelet-derived growth factor C as a mediator of both renal fibrosis and hypertension.

鉴定血小板衍生生长因子 C 作为肾纤维化和高血压的介质

• DOI: 10.1016/j.kint.2018.11.031
• 发表时间: 2019
• 期刊: Kidney international
• 影响因子: 19.6
• 作者: van Roeyen CRC;Martin IV;Drescher A;Schuett KA;Hermert D;Raffetseder U;Otten S;Buhl EM;Braun GS;Kuppe C;Liehn E;Boor P;Weiskirchen R;Eriksson U;Gross O;Eitner F;Floege J;Ostendorf T
• 通讯作者: Ostendorf T