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

除了肾素-血管紧张素系统的抑制剂外，目前只有少数特定的治疗方案存在，它们可以抑制进行性肾脏疾病期间功能性肾单位的损失以及肾纤维化的发展。鉴于急性或慢性肾功能衰竭患者人数不断增加，同时已达到大流行的程度，迫切需要确定新的治疗靶点。在这种情况下，5-羟色胺受体5-HTR-2a和/或-2b引起了极大的兴趣，因为它们的促纤维化作用在皮肤、肺和肝脏等几个器官中都有充分的证据，而且干预的药物选择已经存在。更重要的是，研究表明，阻断受体甚至可以逆转已建立的纤维化。这几乎从未在肾脏中被记录，但将是主要的临床兴趣。关于肾脏血清素系统在急慢性肾脏疾病中的作用，几乎没有资料存在。在广泛的前期研究中，我们获得的数据表明5-HTR-2a和-2b在肾脏中具有促纤维化作用，但也表明其在小管细胞再生中的功能。具体来说，肾脏的这些功能明显不同于其他器官。在本研究中，我们希望验证5-HTR-2a和-2b受体是急性和慢性肾损伤的重要介质的假设，并且体内中和一种或两种受体代表了肾脏疾病的新治疗方法。该假设将通过四种实验方法进行验证：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体外分析，3)5-HTR-2a和-2b在急慢性肾损伤中的病理生理作用研究。最后，5-HTR-2a和/或-2b的体内中和将在早期疾病和已建立的肾纤维化中进行。

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.