Abstract
The Janus kinase (JAK) tyrosine kinase family and JAK/STAT signal transduction pathway may act in kidney fibrogenesis. JAK3 expression was investigated in in vitro and in vivo models of kidney fibrosis involving oxidative stress. There was a marked down-regulation of JAK3 mRNA in rat kidney tubular epithelial cells (NRK52E) and fibroblasts (NRK49F) exposed to 1.0 mM H2O2 for 18–20 h compared with controls, which correlated with increased apoptosis and decreased mitosis in both cell lines. However, JAK3 protein levels were not significantly different in control and H2O2-treated epithelial and fibroblast cultures. JAK3 activation (phospho-tyrosine) increased in NRK52E cells and decreased in NRK49F cells with oxidative stress. STAT3 phosphorylation decreased in both cell lines with oxidative stress compared with controls. JAK3 protein expression and localisation were investigated in kidneys using the unilateral ureteral obstruction (UUO) model (0–7 days, rats) of kidney fibrosis that involves oxidative stress. JAK3 protein expression did not differ between UUO and controls; however, JAK3 localisation increased temporally with UUO, with strong epithelial expression in mitotic cells compared with controls. Apoptotic tubular epithelium showed minimal JAK3. In summary, in vitro, decreased kidney JAK3 mRNA after oxidative stress was not seen translationally. Differences in the activation of the JAK3/STAT3 pathway may have different consequences for renal fibrosis. In vivo, changes in JAK3 protein localisation, and especially its co-localisation with mitotic cells, indicate that JAK3 protein may contribute to renal tubular epithelial cell proliferation after oxidative stress.
Highlights
The Janus kinase (JAK) family of signal transduction molecules consist of non-receptor tyrosine kinases, which are activated in the cytoplasm rather than at the cell membrane [1]
To assess any temporal association between altered JAK3 mRNA (Table 1) and apoptosis or mitosis, percentage change in these parameters was investigated in control, SF and 1.0 mM H O -treated cultures of NRK49F fibroblast and NRF52E tubular epithelial cells at 24 h of treatment
These changes in apoptosis and mitosis with oxidative stress were associated with the decrease in JAK3 mRNA in both cell lines
Summary
The Janus kinase (JAK) family of signal transduction molecules consist of non-receptor tyrosine kinases, which are activated in the cytoplasm rather than at the cell membrane [1]. There are currently four characterised JAK kinases—JAK1, JAK2, JAK3 and TYK2 Nuclear signalling from these kinases is mediated through a group of proteins known as signal transducers and activators of transcription (STAT). Seven members of this family (STAT1-4, STAT5a, STAT5b and STAT6) are tyrosine phosphorylated by JAKs in the Journal of Renal and Hepatic Disorders 2018; 2(1): 18–26. JAK signalling in oxidant-induced kidney fibrosis cytoplasm and proceed to translocate into the nucleus where they act as transcription factors [2]. JAK/ STATs were reported to be activated during pro-inflammatory IL-6-induced proliferation in renal cancer cells [8]. Wiezel et al [10] reported impaired JAK/STAT signalling in chronic kidney disease
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