Proteasome inhibitors in progressive renal diseases

Abstract

Proteasome (PS) is a sophisticated protein degradation machinery comprising a 20S proteolytic core particle provided with caspase-like, trypsin-like and chymotrypsin-like activities on ubiquitinilated proteins. The products of this selective, complex, controlled and strictly coordinated system play a crucial role in cell cycle progression and apoptosis; activation of transcription factors, cytokines and chemokines; degradation and generation of MHC class I-presented peptides. PS has recently emerged as a promising drug target in cancer therapy, and bortezomib has been approved for refractory multiple myeloma. PS proteolysis is crucial for the degradation of the inhibitory protein IkB of nuclear factor kB (NF-kB), and hence, an interesting field of research has been developed on possible benefits of drugs with anti-PS activity in disease conditions with hyper-expression of NF-kB. PS inhibitors are being adopted in pilot studies in antibody-mediated renal rejection and in AL amyloidosis, with increasing scientific interest in possible applications in lupus, IgA nephropathy, idiopathic nephrotic syndrome and renal fibrosis. The most often used PS inhibitor, bortezomib, has a severe peripheral neurotoxicity, and the search for effective and less toxic PS-targeted drugs is a challenging area also in nephrology.