title: SPAK plays a pathogenic role in IgA nephropathy through the activation of NF-κB/MAPKs signaling pathway.
abstract: Sterile 20/SPS1-related proline/alanine-rich kinase (SPAK) can stimulate production of proinflammatory cytokines and interact with inflammation-related molecules. However, it has yet to be determined whether SPAK plays a pathophysiological role in the complicated pathological mechanisms of IgA nephropathy (IgAN), which is mainly characterized by mesangial cell (MC) proliferation and is the most common form of glomerulonephritis. In the present study, we examined the pathophysiological role of SPAK in IgAN using a mouse model and cell models. Our results clearly showed that (1) SPAK deficiency prevents the development of IgAN and inhibits production of immune/inflammatory mediators and T cell activation and proliferation; and (2) when primed with IgA immune complexes (IgA IC), both peritoneal macrophages and primary MCs from SPAK knockout mice show markedly reduced production of proinflammatory cytokines and inhibition of NF-κB/MAPKs activation. We proposed that activation of SPAK and the NF-κB/MAPKs signaling pathway in MCs, macrophages and T cells of the glomerulus may be a mechanism underlying the pathogenesis of IgAN. The activation of SPAK in renal tubuloepithelial cells either directly by IgA IC or an indirect action of the activated MCs or infiltrating mononuclear leukocytes seen in the kidney may further aggravate the disease process of IgAN. Our results suggest that SPAK is a potential therapeutic target for the glomerular disorder.
authors: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors: Tsai-Jung
authors: TJ
authors: Lin
authors: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan; Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Institute of BioMedical Sciences, Academia Sinica, Taipei, Taiwan.
authors: Sung-Sen
authors: SS
authors: Yang
authors: Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan.
authors: Kuo-Feng
authors: KF
authors: Hua
authors: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors: Yu-Ling
authors: YL
authors: Tsai
authors: Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors: Shih-Hua
authors: SH
authors: Lin
authors: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan; Graduate Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan; Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. Electronic address: shukmanka@gmail.com.
authors: Shuk-Man
authors: SM
authors: Ka
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000737:chemistry; D002460:Cell Line; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D005922:Glomerulonephritis, IGA / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D007070:Immunoglobulin A / Q000235:genetics / Q000276:immunology; D007678:Kidney Glomerulus / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D050527:Mesangial Cells / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology*; D061251:Primary Cell Culture; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology
chemical_list: D000936:Antigen-Antibody Complex; D007070:Immunoglobulin A; D016328:NF-kappa B; C486407:Stk39 protein, mouse; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: IgA immune complexes; IgA nephropathy; Knockout mice; Macrophages; Mesangial cells; NF-κB/MAPKs signaling; Sterile 20/SPS1-related proline/alanine-rich kinase; T cells