title: NF-κB-inducing kinase increases renal tubule epithelial inflammation associated with diabetes.
abstract: The impact of increased NF-κB-inducing kinase (NIK), a key component of the NF-κB activation pathways, on diabetes-induced renal inflammation remains unknown. We overexpressed NIK wild type (NIKwt) or kinase-dead dominant negative mutants (NIKdn) in HK-2 cells and demonstrated that RelB and p52, but not RelA, abundance and DNA binding increased in nuclei of NIKwt but not NIKdn overexpressed cells, and this corresponded with increases in multiple proinflammatory cytokines. Since TRAF3 negatively regulates NIK expression, we silenced TRAF3 by >50%; this increased nuclear levels of p52 and RelB, and transcript levels of proinflammatory cytokines and transcription factors. In HK-2 cells and mouse primary proximal tubule epithelial cells treated with methylglyoxal-modified albumin, multiple proinflammatory cytokines and NIK were increased in association with increased nuclear RelB and p52. These observations indicate that NIK regulates proinflammatory responses of renal proximal tubular epithelial cells via mechanisms involving TRAF3 and suggest a role for NF-κB noncanonical pathway activation in modulating diabetes-induced inflammation in renal tubular epithelium.
authors.affiliation: Division of Endocrinology and Stark Diabetes Center, Department of Internal Medicine, The University of Texas Medical Branch, 301 University Baulevard, Galveston, TX 77555-1060, USA.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Zhao
authors.forename: Srijita
authors.initials: S
authors.lastname: Banerjee
authors.forename: Wanda S
authors.initials: WS
authors.lastname: LeJeune
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Choudhary
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Tilton
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009393:Nephritis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011765:Pyruvaldehyde / Q000737:chemistry / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D012709:Serum Albumin / Q000737:chemistry / Q000494:pharmacology; D014162:Transfection; D019459:Urothelium / Q000378:metabolism / Q000473:pathology*; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D017346:Protein Serine-Threonine Kinases; D011765:Pyruvaldehyde; D034741:RNA, Small Interfering; D012709:Serum Albumin; D000097782:NF-kappaB-Inducing Kinase