Neutrophil Extracellular Traps in the Establishment and Progression of Renal Diseases

Abstract

Uncontrolled inflammatory and immune responses are often involved in the development of acute and chronic forms of renal injury. Neutrophils are innate immune cells recruited early to sites of inflammation, where they produce pro-inflammatory cytokines and release mesh-like structures comprised of DNA and granular proteins known as neutrophil extracellular traps (NETs). NETs are potentially toxic, contribute to glomerular injury, activate autoimmune processes, induce vascular damage, and promote kidney fibrosis. Evidence from multiple studies suggests that an imbalance between production and clearance of NETs is detrimental for renal health. Hence strategies aimed at modulating NET-associated processes could have a therapeutic impact on a myriad of inflammatory diseases that target the kidney. Here, we summarize the role of NETs in the pathogenesis of renal diseases and their mechanisms of tissue damage.

Keywords: AKI; NETosis; NETs; autoimmunity; kidney; neutrophils; vasculitis.

Figure 1

NETosis in Renal Disease. Neutrophil activation can lead to the release of NETs, mesh-like structures comprised of DNA and polymorphonuclear proteins such as myeloperoxidase (MPO), neutrophil elastase (NE) and citrullinated histones H3. NETs produce tissue damage through DNA, histones, neutrophil elastase, autoantibodies and complement activation. Moreover, NETs are involved in autoimmune and inflammatory diseases that damage the kidney such as acute kidney injury, lupus nephritis, small vessel and ANCA-associated vasculitis.

Figure 2

NET-associated mechanisms of tissue damage in kidney disease. The balance between NET release/NET degradation is relevant in the establishment and progression of multiple kidney diseases including acute kidney injury (AKI), lupus nephritis, small vessel vasculitis (SVV) and ANCA-associated vasculitis (AAV). Circulation: Netting neutrophils are in the circulation, along with decondensed DNA and NETosis markers detected in serum such as ANCA-MPO, ANCA-PR3, citrullinated histone H3, peptidyl arginine deiminase 4 (PAD4), and DNase I inhibitors that impair NET degradation. Kidney: Neutrophils can infiltrate the kidney in response to pro-inflammatory stimuli. Here, they can release NETs and NET components such as histones that are cytotoxic and promote pro-fibrotic phenotypes. Oxidative stress, inflammation, protein citrullination, and autophagy are molecular mechanisms closely linked to NET formation. Indirect tissue injury by NETs can result in fibrosis, autoimmunity, and a decrease in renal function.