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

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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.