Role of JAK3 in the Pathogenesis of Oxidative Stress-Induced Kidney Fibrosis

Main Article Content

Betty Pat
David W Johnson
Glenda C Gobe

Keywords

JAK3, Janus kinase tyrosine kinase family, kidney fibrosis, oxidative stress, STAT

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.

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References

1. Chuang PY, He JC. JAK/STAT signaling in renal diseases. Kidney Int. 2010 Aug;78(3):231–4. http://dx.doi.org/10.1038/ki.2010.158
2. Matsui F, Meldrum KK. The role of the Janus kinase family/signal transducer and activator of transcription signaling pathway in fibrotic renal disease. J Surg Res. 2012 Nov;178(1):339–45. http://dx.doi.org/10.1016/j.jss.2012.06.050
3. Guh JY, Huang JS, Chen HC, Hung WC, Lai YH, Chuang LY. Advanced glycation end product-induced proliferation in NRK-49F cells is dependent on the JAK2/STAT5 pathway and cyclin D1. Am J Kidney Dis. 2001 Nov;38(5):1096–104. http://dx.doi.org/10.1053/ajkd.2001.28616
4. Koike K, Ueda S, Yamagishi S, Yasukawa H, Kaida Y, Yokoro M, et al. Protective role of JAK/STAT signaling against renal fibrosis in mice with unilateral ureteral obstruction. Clin Immunol. 2014 Jan;150(1):78–87. http://dx.doi.org/10.1016/j.clim.2013.11.003
5. Huang JS, Guh JY, Hung WC, Yang ML, Lai YH, Chen HC, et al. Role of the Janus kinase (JAK)/signal transducters and activators of transcription (STAT) cascade in advanced glycation end-product-induced cellular mitogenesis in NRK-49F cells. Biochem J. 1999 Aug 15;342 (Pt 1):231–8. http://dx.doi.org/10.1042/bj3420231
6. Huang JS, Guh JY, Chen HC, Hung WC, Lai YH, Chuang LY. Role of receptor for advanced glycation end-product (RAGE) and the JAK/STAT-signaling pathway in AGE-induced collagen production in NRK-49F cells. J Cell Biochem. 2001;81(1):102–13. http://dx.doi.org/10.1002/1097-4644(20010401)81:1%3C102::AID-JCB1027%3E3.0.CO;2-Y
7. Pang M, Ma L, Gong R, Tolbert E, Mao H, Ponnusamy M, et al. A novel STAT3 inhibitor, S3I-201, attenuates renal interstitial fibroblast activation and interstitial fibrosis in obstructive nephropathy. Kidney Int. 2010 Aug;78(3):257–68. http://dx.doi.org/10.1038/ki.2010.154
8. Horiguchi A, Oya M, Marumo K, Murai M. STAT3, but not ERKs, mediates the IL-6-induced proliferation of renal cancer cells, ACHN and 769P. Kidney Int. 2002 Mar;61(3):926–38. http://dx.doi.org/10.1046/j.1523-1755.2002.00206.x
9. Dai T, Wang Y, Nayak A, Nast CC, Quang L, LaPage J, et al. Janus kinase signaling activation mediates peritoneal inflammation and injury in vitro and in vivo in response to dialysate. Kidney Int. 2014 Dec;86(6):1187–96. http://dx.doi.org/10.1038/ki.2014.209
10. Wiezel D, Assadi MH, Landau D, Troib A, Kachko L, Rabkin R, et al. Impaired renal growth hormone JAK/STAT5 signaling in chronic kidney disease. Nephrol Dial Transplant. 2014 Apr;29(4):791–9. http://dx.doi.org/10.1093/ndt/gfu003
11. Pat BK, Cuttle L, Watters D, Yang T, Johnson DW, Gobe GC. Fibrogenic stresses activate different mitogen-activated protein kinase pathways in renal epithelial, endothelial or fibroblast cell populations. Nephrology (Carlton). 2003 Aug;8(4):196–204. http://dx.doi.org/10.1046/j.1440-1797.2003.00162.x
12. Pat B, Yang T, Kong C, Watters D, Johnson DW, Gobe G. Activation of ERK in renal fibrosis after unilateral ureteral obstruction: Modulation by antioxidants. Kidney Int. 2005 Mar;67(3):931–43. http://dx.doi.org/10.1111/j.1523-1755.2005.00157.x
13. Han Y, Masaki T, Hurst LA, Ikezumi Y, Trzaskos JM, Atkins RC, et al. Extracellular signal-regulated kinase-dependent interstitial macrophage proliferation in the obstructed mouse kidney. Nephrology (Carlton). 2008 Oct;13(5):411–18. http://dx.doi.org/10.1111/j.1440-1797.2008.00926.x
14. Percy CJ, Pat BK, Healy H, Johnson DW, Gobe GC. Phosphorylation of caveolin-1 is anti-apoptotic and promotes cell attachment during oxidative stress of kidney cells. Pathology. 2008 Dec;40(7):694–701. http://dx.doi.org/10.1080/00313020802436402
15. Gobe G. Identification of apoptosis in kidney tissue sections. Methods Mol Biol. 2009;466:175–92. http://dx.doi.org/10.1007/978-1-59745-352-3_13
16. Davidson K, Percy C, Rennick AJ, Pat BK, Li J, Nicol D, et al. Comparative analysis of caspase activation and apoptosis in renal tubular epithelial cells and renal cell carcinomas. Nephron Exp Nephrol. 2005;99(4):e112–20. http://dx.doi.org/10.1159/000083926
17. Rajandram R, Yap NY, Pailoor J, Razack AH, Ng KL, Ong TA, et al. Tumour necrosis factor receptor-associated factor-1 (TRAF-1) expression is increased in renal cell carcinoma patient serum but decreased in cancer tissue compared with normal: Potential biomarker significance. Pathology. 2014 Oct;46(6):518–22. http://dx.doi.org/10.1097/PAT.0000000000000145
18. Liu Q, Xing L, Wang L, Yao F, Liu S, Hao J, et al. Therapeutic effects of suppressors of cytokine signaling in diabetic nephropathy. J Histochem Cytochem. 2014 Feb;62(2):119–28.
19. Bhattacharjee N, Barma S, Konwar N, Dewanjee S, Manna P. Mechanistic insight of diabetic nephropathy and its pharmacotherapeutic targets: An update. Eur J Pharmacol. 2016 Nov 15;791:8–24. http://dx.doi.org/10.1016/j.ejphar.2016.08.022
20. Viengchareun S, Lema I, Lamribet K, Keo V, Blanchard A, Cherradi N, et al. Hypertonicity compromises renal mineralocorticoid receptor signaling through Tis11b-mediated post-transcriptional control. J Am Soc Nephrol. 2014 Oct;25(10):2213–21. http://dx.doi.org/10.1681/ASN.2013091023
21. Chen SC, Guh JY, Chen HC, Yang YL, Huang JS, Chuang LY. Advanced glycation end-product-induced mitogenesis is dependent on Janus kinase 2-induced heat shock protein 70 in normal rat kidney interstitial fibroblast cells. Transl Res. 2007 May;149(5):274–81. http://dx.doi.org/10.1016/j.trsl.2006.08.005
22. Brosius FC, Khoury CC, Buller CL, Chen S. Abnormalities in signaling pathways in diabetic nephropathy. Expert Rev Endocrinol Metab. 2010;5(1):51–64. http://dx.doi.org/10.1586/eem.09.70
23. Khan SS, Quaggin SE. Therapies on the horizon for diabetic kidney disease. Curr Diab Rep. 2015 Dec;15(12):111. http://dx.doi.org/10.1007/s11892-015-0685-3
24. Choi EA, Lei H, Maron DJ, Wilson JM, Barsoum J, Fraker DL, et al. Stat1-dependent induction of tumor necrosis factor-related apoptosis-inducing ligand and the cell-surface death signaling pathway by interferon beta in human cancer cells. Cancer Res. 2003 Sep 1;63(17):5299–307.
25. Digicaylioglu M, Lipton SA. Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades. Nature. 2001 Aug 9;412(6847):641–7. http://dx.doi.org/10.1038/35088074
26. Peake JM, Gobe GC, Fassett RG, Coombes JS. The effects of dietary fish oil on inflammation, fibrosis and oxidative stress associated with obstructive renal injury in rats. Mol Nutr Food Res. 2011 Mar;55(3):400–10. http://dx.doi.org/10.1002/mnfr.201000195