ProjectBedeutung des alternativen Komplementwegs beim nephrotischen Syndrom

Basic data

Title:
Bedeutung des alternativen Komplementwegs beim nephrotischen Syndrom
Duration:
5/3/2021 to 5/2/2024
Abstract / short description:
The epithelial sodium channel (ENaC) is expressed in the late distal aldosterone-sensitive tubule and is of essential importance for the sodium homeostasis. Among the various regulatory mechanisms of ENaC, activation after proteolytic cleavage by intra- and extracellular serine proteases is a specific feature of ENaC. Nephrotic syndrome leads to sodium retention and edema formation and is mediated by increased ENaC activity due to aberrantly filtered serine proteases from the plasma which activate ENaC by proteolysis. The relevance of this mechanism was demonstrated in vivo by the applicant whereby the unselective serine protease inhibitor aprotinin protected nephrotic mice from sodium retention and edema formation. Since this pivotal finding, the applicant´s group – supported by DFG grants AR 1092/1 and AR 1092/2 - focuses on the identification of the essential serine protease(s) from urine samples of mice and humans that might be involved in proteolytic ENaC activation. Using a proteomic approach several serine proteases were identified and tested for their pathophysiological relevance in nephrotic knockout mouse models. Currently, involvement of urokinase, plasmin, plasma kallikrein, coagulation factor XII, Factor VII-activating protease as well as prostasin was excluded. In addition, nephrotic urine samples contained the serine proteases complement factor D and B which are part of the alternative complement pathway and could also play a significant role. Moreover, there was evidence of activation of the alternative complement pathway in nephrotic samples from humans and mice. In accordance with a possible relevance of this pathway, the cleavage sequence of CFD at this physiological substrate CFB is identical with that of the γ-subunit of ENaC which was determined by own experiments with a substrate approach. In this project, the applicant aims to elucidate the role of the alternative complement pathway in sodium retention and edema formation in nephrotic syndrome. To this end, comprehensive analysis of complement factors and activation will be established in nephrotic urine samples. The in vivo relevance will be investigated using nephrotic mouse models involving knockout mice with deletion of the essential components of alternative complement pathway (CFD, CFB, C3, properdin). This identification of the alternative complement pathway as cause of proteolytic ENaC activation may lay the foundation to develop a therapeutic strategy in nephrotic syndrome.
Keywords:
nephrotisches Syndrom
Alternativer Komplementweg
epithelialer Natriumkanal ENaC
Proteasurie

Involved staff

Managers

Faculty of Medicine
University of Tübingen

Local organizational units

Internal Medicine Department IV
Department of Internal Medicine
Hospitals and clinical institutes, Faculty of Medicine

Funders

Bonn, Nordrhein-Westfalen, Germany
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