NETosis: an emerging therapeutic target in renal diseases

Abstract

IntroductionNeutrophil extracellular traps (NETs) are web-like structures composed of nuclear and granular components. The primary role of NETS is to prevent the dissemination of microbes and facilitate their elimination. However, this process is accompanied by collateral proinflammatory adverse effects when the NET release becomes uncontrollable, or clearance is impaired. Although NET-induced organ damage is conducted primarily and indirectly via immune complexes and the subsequent release of cytokines, their direct effects on cells are also remarkable. NETosis plays a critical pathogenic role in several renal disorders, such as the early phase of acute tubular necrosis, anti-neutrophil cytoplasmic antibody-mediated renal vasculitis, lupus nephritis, thrombotic microangiopathies, anti-glomerular basement membrane disease, and diabetic nephropathy. Their substantial contribution in the course of these disorders makes them a desirable target in the therapeutic armamentarium. This article gives an in-depth review of the heterogeneous pathogenesis and physiological regulations of NETosis and its pivotal role in renal diseases. Based on the pathogenesis, the article also outlines the current therapeutic options and possible molecular targets in the treatment of NET-related renal disorders.MethodsWe carried out thorough literature research published in PubMed and Google Scholar, including a comprehensive review and analysis of the classification, pathomechanisms, and a broad spectrum of NET-related kidney disorders.ConclusionsNETosis plays a pivotal role in certain renal diseases. It initiates and maintains inflammatory and autoimmune disorders, thus making it a desirable target for improving patient and renal outcomes. Better understanding and clinical translation of the pathogenesis are crucial aspects to treatment, for improving patient, and renal outcomes.

Unveiling the pathogenesis and therapeutic approaches for diabetic nephropathy: insights from panvascular diseases

“…NETosis, the formation of neutrophil extracellular traps (NETs), plays a significant role in the pathogenesis of DN ( 95 ). While inflammation and oxidative stress are known contributors to DN, the involvement of neutrophils has been largely overlooked.…”

Targeting Neutrophil Extracellular Trap Formation: Exploring Promising Pharmacological Strategies for the Treatment of Preeclampsia

“…Furthermore, drugs such as Hydroxychloroquine (HCQ) [91], PF3758309, and IPA-3 inhibit NETs through Rac2 [92]. Chloroquine (CQ) and HCQ can prevent NET formation by inhibiting PAD4 [93] or TLR signalling as with HCQ, CQ, and enpatoran [94]. In Amid the COVID-19 pandemic, there has been a surge in accelerated investigations on drugs and molecules repurposed for their potential to inhibit NETs, as summarized in Table 1.…”

“…Furthermore, drugs such as Hydroxychloroquine (HCQ) [91], PF3758309, and IPA-3 inhibit NETs through Rac2 [92]. Chloroquine (CQ) and HCQ can prevent NET formation by inhibiting PAD4 [93] or TLR signalling as with HCQ, CQ, and enpatoran [94]. In addition, PDE4 inhibitors such as apremilast, rolipram, and crisaborole can reduce the formation of NETs [95].…”

Macrophage subpopulations in pediatric patients with lupus nephritis and other inflammatory diseases affecting the kidney

“…Currently, anti-inflammatory therapies such as glucocorticoids like prednisone; anti-malarials or immunosuppressants like cyclophoshamide, azathioprine, mycophenolate mofetil, and cyclosporine; or removal of harmful autoantibodies using plasmapheresis are used in the therapy of LN [ 16 ]. As targeted therapies, B-cell depletion with rituximab are still used [ 16 ] and targeting of other immune cells such as neutrophils, e.g., neutrophil extracellular traps, is discussed [ 17 ]. However, macrophage-specific therapies are not yet available.…”