title: Endogenous NAMPT dampens chemokine expression and apoptotic responses in stressed tubular cells.
abstract: Diabetic nephropathy (DN) is the most common cause of end-stage renal disease and identification of new therapeutic targets is needed. Nicotinamide phosphoribosyltransferase (NAMPT) is both an extracellular and intracellular protein. Circulating NAMPT is increased in diabetics and in chronic kidney disease patients. The role of NAMPT in renal cell biology is poorly understood. NAMPT mRNA and protein were increased in the kidneys of rats with streptozotocin-induced diabetes. Immunohistochemistry localized NAMPT to glomerular and tubular cells in diabetic rats. The inflammatory cytokine TNFα increased NAMPT mRNA, protein and NAD production in cultured kidney human tubular cells. Exogenous NAMPT increased the mRNA expression of chemokines MCP-1 and RANTES. The NAMPT enzymatic activity inhibitor FK866 prevented these effects. By contrast, FK866 boosted TNFα-induced expression of MCP-1 and RANTES mRNA and endogenous NAMPT targeting by siRNA also had a proinflammatory effect. Furthermore, FK866 promoted tubular cell apoptosis in an inflammatory milieu containing the cytokines TNFα/IFNγ. In an inflammatory environment FK866 promoted tubular cell expression of the lethal cytokine TRAIL. These data are consistent with a role of endogenous NAMPT activity as an adaptive, protective response to an inflammatory milieu that differs from the proinflammatory activity of exogenous NAMPT. Thus, disruption of endogenous NAMPT function in stressed cells promotes tubular cell death and chemokine expression. This information may be relevant for the design of novel therapeutic strategies in DN.
authors.affiliation: Instituto de Investigaciones Sanitarias - Fundación Jimenez Diaz-Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Benito-Martin
authors.affiliation: Instituto de Investigaciones Sanitarias - Fundación Jimenez Diaz-Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Alvaro C
authors.initials: AC
authors.lastname: Ucero
authors.affiliation: Instituto de Investigaciones Sanitarias - Fundación Jimenez Diaz-Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: María Concepción
authors.initials: MC
authors.lastname: Izquierdo
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols", CSIC, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Santamaria
authors.affiliation: Instituto de Investigaciones Sanitarias - Fundación Jimenez Diaz-Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Picatoste
authors.affiliation: Instituto de Investigaciones Sanitarias - Fundación Jimenez Diaz-Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Carrasco
authors.affiliation: Instituto de Investigaciones Sanitarias - Fundación Jimenez Diaz-Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Lorenzo
authors.affiliation: Instituto de Investigaciones Sanitarias - Fundación Jimenez Diaz-Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
authors.affiliation: Instituto de Investigaciones Sanitarias - Fundación Jimenez Diaz-Universidad Autónoma de Madrid, Fundacion Renal Iñigo Alvarez de Toledo-IRSIN, Madrid, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Egido
authors.affiliation: Instituto de Investigaciones Sanitarias - Fundación Jimenez Diaz-Universidad Autónoma de Madrid, Fundacion Renal Iñigo Alvarez de Toledo-IRSIN, Spain. Electronic address: aortiz@fjd.es.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
mesh_terms: D000178:Acrylamides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D015153:Blotting, Western; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D018925:Chemokines / Q000235:genetics* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000166:cytology*; D009243:NAD / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D011921:Rats, Inbred WKY; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000178:Acrylamides; C111835:CCL2 protein, human; C483024:CCL5 protein, human; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D018925:Chemokines; D015850:Interleukin-6; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; D014409:Tumor Necrosis Factor-alpha; D009243:NAD; D054409:Nicotinamide Phosphoribosyltransferase
keywords: Apoptosis; Diabetes; Inflammation; Kidney; NAMPT