JAK3 EXPRESSION IN GLOMERULAR EPITHELIA OF IGA NEPHROPATHY (IGA-N) PATIENTS

Jak3 is a member of the Janus kinase family which plays an important r ole in cytokine signal transduction. Jak3 associates the gamma(c) chai n 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 ex pression of Jak3 in glomeruli in vivo. To investigate the physiologica l and pathological role of Jak3 in glomeruli, we prepared anti-Jak3 an tibody and analysed the localization of Jak3 in glomeruli of renal bio psy samples from various nephritis patients and normal subjects. Among 61 nephritis patients and four normal subjects investigated in the pr esent study, Jak3 was selectively localized to glomerular epithelia of IgA-N patients (14/34 cases) and focal glomerulosclerosis patients (1 /5 cases), but not detected in minimal changes (n = 6), membranous glo merulonephropathy (n = 7), crescentic glomerulonephritis (n = 4), lupu s nephritis patients (n = 5), and normal subjects (n = 4). The intense immunoreactivity for Jak3 is significantly associated with the decrea se in creatinine clearance (81.5 +/- 10.4 ml/min versus 104.3 +/- 29.6 ml/min; P < 0.05, Student's t-test) and the increase in level of seru m creatinine (1.13 +/- 0.33 mg/dl versus 0.75 +/- 0.23 mg/dl; P < 0.01 , Student's t-test) in IgA-N patients. Furthermore, gamma(c) chain was concomitantly ex pressed with Jak3 in glomerular epithelia in vivo an d in vitro, suggesting that signal transduction via gamma(c)-Jak3 casc ade may be involved in the pathogenesis of glomerular injury of IgA-N. Taken together with the recent findings that IL-4-secreting T lymphoc ytes in affected glomeruli injure glomerular epithelium, the responsiv eness of glomerular epithelium for IL-4 may be pathologically enhanced in IgA-N.