Impaired systemic proteostasis and peripheral immune cell dysfunction in kidney diseases

Abstract

ABSTRACT Kidney diseases, encompassing a spectrum of either acute or chronic disorders, manifest complex systemic repercussions beyond renal dysfunction. These include a reduced efficacy of tissue proteostasis mechanisms to control protein synthesis, folding, and degradation in both the renal and extra-renal compartments. Emerging research has revealed a pivotal interplay between proteostasis and immune regulation in the pathogenesis of kidney diseases, along with their cardiovascular, immunometabolic, and organ dysfunction symptoms. This review outlines the multifaceted connections between proteostasis dysregulation and immune dysfunction in kidney disease onset and progression. The crosstalk between the proteostasis network and immune cells orchestrates a bidirectional communication that amplifies pathological cascades, exacerbating kidney injury and impairing organ resilience. Furthermore, the article focuses on the implications of systemic proteostasis defects in modulating immune responses in extra-renal tissues underscore the systemic nature of kidney diseases. The disruption of proteostasis mechanisms triggers the release of damage-associated molecular patterns (DAMPs) and inflammatory mediators, perpetuating a state of heightened immune activation, contributing to systemic complications in affected individuals. Understanding the intricate interaction between proteostasis and immune regulation in kidney diseases, including both chronic and acute forms, promises novel therapeutic interventions. Targeting proteostasis pathways to restore cellular homeostasis and modulating immune responses could offer innovative strategies to mitigate renal damage and ameliorate systemic complications associated with kidney diseases. Harnessing this knowledge may also pave the way for the development of more efficient dialysis therapies and interventions with sorbents and hemoperfusion methods, to improve the clinical outcome of the patients.