Spleen Tyrosine Kinase: A Crucial Player and Potential Therapeutic Target in Renal Disease

Abstract

Spleen tyrosine kinase (Syk), a 72 kDa cytoplasmic non-receptor protein-tyrosine kinase, plays an important role in signal transduction in a variety of cell types. Ever since its discovery in the early 1990s, there has been accumulating evidence to suggest a pathogenic role of Syk in various allergic disorders, autoimmune diseases and malignancies. Additionally, there is emerging data from both pre-clinical and clinical studies that Syk is implicated in the pathogenesis of proliferative glomerulonephritis (GN), including anti-glomerular basement membrane disease, anti-neutrophil cytoplasmic antibody-associated GN, lupus nephritis and immunoglobulin A nephropathy (IgAN). Moreover, recent animal studies have shed light on the importance of Syk in mediating acute renal allograft rejection, Epstein Barr virus-associated post-transplant lymphoproliferative disease and kidney fibrosis. Fostamatinib, an oral Syk inhibitor, has undergone clinical testing in rheumatoid arthritis, refractory immune thrombocytopenic purpura, leukemia and lymphoma. The recent STOP-IgAN trial showed that the addition of non-selective immunosuppressive therapy to intensive supportive care did not improve clinical outcomes in high-risk IgAN patients. A Syk-targeted approach may be beneficial and is currently being evaluated in a phase II randomized controlled trial. In this review, we will discuss the pathogenic role of Syk and potential use of Syk inhibitor in a variety of renal diseases.

High-Throughput Phenotypic Screening of Kinase Inhibitors to Identify Drug Targets for Polycystic Kidney Disease

“…Syk may represent an interesting target for various renal diseases. 36 However, R788 (fostamatinib) and its active metabolite R406 may also inhibit fms-like tyrosine kinase 3 (Flt3) at the tested concentrations, so their inhibitory activity may not be solely due to inhibition of Syk ( Suppl. Table S4 ; also quizartinib, an inhibitor of Flt3, displays inhibitory activity as shown in Fig.…”

Spleen Tyrosine Kinase Inhibition Ameliorates Tubular Inflammation in IgA Nephropathy

“…Recent advance in the development of grouped ddY mouse model of IgAN may be a useful tool for future investigation (Suzuki et al, 2014). Furthermore, a phase II randomized controlled trial has been conducted to evaluate the efficacy and safety of fostamatinib in treatment of patients with IgAN (Ma et al, 2016).…”

Characterizing the structure–activity relationships of natural products, tanshinones, reveals their mode of action in inhibiting spleen tyrosine kinase

“… 29 SYK was firstly discovered in 1990s, and several evidence suggest that SYK was highly associated with various autoimmune disease and allergic disorders. 30 SYK is widely express in macrophages, dendritic cells, mast cells, neutrophils, B and T lymphocytes. 31–33 The activations of SYK in immune cells prompts B-cell are involved inflammation, proliferation, cytokine release, and cytoskeletal rearrangements.…”