Uremic plasma proteins accumulate in peripheral blood mononuclear leukocytes inducing apoptosis: insights in the immuno-proteostasis response of chronic kidney disease.

Abstract

Abstract Peripheral blood mononuclear leukocytes (PBL) of uremic patients (u-PBL) prematurely die by apoptosis, thus sustaining leukopenia and immune dysfunction. Uremic retention solutes have been alleged to playing a causal role in this immune cell defect. However, both the molecular identity and pro-apoptotic mechanism of these solutes remain poorly characterized. In this study, we prepared a fraction of the uremic plasma (u-Pl) rich in these solutes (proteinaceous material with molecular weight > 50 kDa, namely the uremic-high MW fraction or u-HMW) that was used to demonstrate their pro-apoptotic activity in u-PBL. Such a detrimental activity was also confirmed in THP-1 and K562 mononuclear cells in association with increased cellular generation and secretion of H2O2, and JNK/cJun-dependent apoptotic signaling downstream of the endoplasmic reticulum stress response protein IRE1-α. The u-HMW also induced autophagy in THP-1 mononuclear leukocytes. These alterations of u-PBL proteostasis were associated with the presence in the proteome of these cells, but not of control PBL, of the main proteins and protein decoration targets (assessed by 2,4-diphenylhydrazine derivatization) of u-Pl and thus of u-HMW, namely albumin, transferrin and fibrinogen. These findings demonstrate that large solutes induce apoptosis in u-PBL leading to abnormal plasma protein endocytosis and terminal alteration of cellular proteostasis mechanisms. We define this response of PBL to large uremic solutes as the “immuno-proteostasis response” (IPR) of uremia.