Basic Research
Correlation of disease activity in proliferative glomerulonephritis with glomerular spleen tyrosine kinase expression

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Spleen tyrosine kinase (SYK) is an important component of the intracellular signaling pathway for various immunoreceptors. Inhibition of SYK has shown promise in preclinical models of autoimmune and glomerular disease. However, the description of SYK expression in human renal tissue, which would be desirable ahead of clinical studies, is lacking. Here we conducted immunohistochemical analysis for total and phosphorylated SYK in biopsy specimens from >120 patients with a spectrum of renal pathologies, including thin basement membrane lesion, minimal change disease, membranous nephropathy, IgA nephropathy, lupus nephritis, ANCA-associated glomerulonephritis, antiglomerular basement membrane disease, and acute tubular necrosis. We found significant SYK expression in proliferative glomerulonephritis and that glomerular expression levels correlated with presenting serum creatinine and histological features of disease activity that predict outcome in IgA nephropathy, lupus nephritis, ANCA-associated glomerulonephritis, and antiglomerular basement membrane disease. SYK was phosphorylated within pathological lesions, such as areas of extracapillary and endocapillary proliferation, and appeared to localize to both infiltrating leucocytes and to resident renal cells within diseased glomeruli. Thus SYK is associated with the pathogenesis of proliferative glomerulonephritides, suggesting that these conditions may respond to SYK inhibitor treatment.

KEYWORDS

ANCA
anti-GBM disease
glomerulonephritis
IgA nephropathy
immunohistochemistry
lupus nephritis

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FWKT has received research project grants from AstraZeneca and has a consultancy agreement with Rigel Pharmaceuticals. CDP has received a research project grant from GlaxoSmithKline and has a consultancy agreement with Genzyme. The remaining authors declared no competing interests.

This work was presented in abstract form at the American Society of Nephrology Renal Week Meeting in Atlanta, GA, USA in November 2013 and at the UK Renal Association meeting in Glasgow, Scotland in May 2014.