Jak Tyrosine Kinases in IgA Nephropathy

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Jak3 is a member of Janus Kinase which play an important role in cytokine signal transductions. Jak3 associates gamma<@D2c@>D2 chain of receptors for IL-2, IL-4, IL-7, IL-9, and IL-15, and is essential for the signal transduction of these cytokines. We have isolated Jak3 kinase from renal mesangial cells and demonstrated the constitutive expression of Jak3 in glomeruli in vivo. To investigate the physiological and pathological role of Jak3 in glomeruli, we prepared anti-Jak3 antibody and analyzed the localization of Jak3 in glomeruli of renal biopsy samples from various nephritis patients and normal subjects. Among 61 nephritis patients and 4 normal subjects investigated in the present study, Jak3 is selectively localized to glomerular epithelia of IgA nephropathy patients (14/34 cases) and focal glomerulosclerosis patients (1/5 cases), but not detected in minimal changes (6 cases), membranous glomerulonephropathy (7 cases), crescentic glomerulonephritis (4 cases), lupus nephritis patients (5 cases), and normal subjects (4 cases). The intense immunoreactivity for Jak3 is significantly associated with the decrease in creatinine clearance (81.5 (]SY+-[) 10.4 vs 104.3 (]SY+-[) 29.6ml/min, P<0.05, Student's t-test) and the increase in the level of serum creatinine (1.13 (]SY+-[) 0.33 vs 0.75 (]SY+-[) 0.23 mg/dl, P<0.01, Student's t-test) in IgA nephropathy patients. Furthermore, gamma<@D2c@>D2 chain was concomitantly expressed with Jak3 in glomerular epithelia in vivo and in vitro, suggesting that the signal transduction via gamma<@D2c@>D2-Jak3 cascade may be involved in the pathogenesis of glomerular injury of IgA nephropathy. Taken together with the recent findings that IL-4 secreting T lymphocytes in affected glomeruli injure glomerular epithelium, the responsiveness of glomerular epithelium for IL-4 may be pathologically enhanced in IgA nephropathy.