Membranous nephropathy (MN) is the most common cause of adult nephrotic syndrome. Primary MN is characterized by circulating autoantibodies against podocyte antigens, such as the phospholipase A2 receptor (PLA2R1) or the thrombospondin type -1 domain- containing 7A (THSD7A), and an increased expression of PLA2R1 and THSD7A protein but not transcript in podocytes. We demonstrated that persistent podocyte injury in human and rodent MN was characterized by an upregulation of proteolytic systems such as the ubiquitin proteasome system (UPS) in podocytes. With disease progression, the UPS was overwhelmed, resulting in an accumulation of damaged and poly-ubiquitinated proteins in podocytes. The ubiquitin-C-terminal hydrolase-L1 (UCH-L1), a central de-ubiquitinating enzyme of the neuronal UPS, was de novo expressed in podocytes in human and rodent MN. There, UCH-L1 was involved in the accumulation of proteins in the cytoplasm of injured podocytes. Chemical inhibition of UCH-L1 hydrolysis function ameliorated proteinuria and decreased protein accumulation in rodent MN, suggesting that influencing specific UPS components could be a new therapeutic option in MN.
In this project, we plan to connect these observations by addressing the functional role of the UPS, specifically of the proteasome and of proteasome activators, in orchestrating podocyte injury. In patients with MN and in two mouse models of proteinuric glomerulopathy, we will investigate the significance of the UPS for the diagnosis and course of disease. Furthermore, we will study the involvement of the UPS in THSD7A homeostasis in affected podocytes. Our studies will result in a better understanding of the role of the UPS in MN.
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