Jak Tyrosine Kinases in IgA Nephropathy

Jak3是Janus激酶的一个成员，在细胞因子信号转导中起重要作用。Jak3结合IL-2、IL-4、IL-7、IL-9和IL-15的γ <@D2c@>D2受体链，对这些细胞因子的信号转导至关重要。我们从肾系膜细胞中分离出Jak3激酶，并在体内证实了Jak3在肾小球中的组成性表达。为了研究Jak3在肾小球中的生理和病理作用，我们制备了抗Jak3抗体，并分析了不同肾炎患者和正常人肾活检样本中Jak3在肾小球中的定位。本研究调查的61例肾炎患者和4例正常人中，Jak3选择性定位于IgA肾病患者（14/34例）和局灶性肾小球硬化患者（1/5例）的肾小球上皮，而在微小变化（6例）、膜性肾小球肾病（7例）、新月形肾小球肾炎（4例）、狼疮性肾炎（5例）和正常人（4例）中未检测到。Jak3强烈的免疫反应性与IgA肾病患者肌酐清除率降低(81.5 （]SY+-[) 10.4 vs 104.3 (]SY+-[) 29.6ml/min， P<0.05, Student’st检验）和血清肌酐水平升高(1.13 （]SY+-[) 0.33 vs 0.75 (]SY+-[) 0.23 mg/dl， P<0.01, Student’st检验）显著相关。此外，在体内和体外实验中，肾小球上皮细胞中γ <@D2c@>D2链与Jak3同时表达，提示通过γ <@D2c@>D2-Jak3级联的信号转导可能参与了IgA肾病肾小球损伤的发病机制。近期研究发现，病变肾小球中分泌IL-4的T淋巴细胞会损伤肾小球上皮，因此，IgA肾病患者肾小球上皮对IL-4的反应性可能在病理上增强。

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.