title: NF-κB activation mediates crystal translocation and interstitial inflammation in adenine overload nephropathy.
abstract: Adenine overload promotes intratubular crystal precipitation and interstitial nephritis. We showed recently that these abnormalities are strongly attenuated in mice knockout for Toll-like receptors-2, -4, MyD88, ASC, or caspase-1. We now investigated whether NF-κB activation also plays a pathogenic role in this model. Adult male Munich-Wistar rats were distributed among three groups: C (n = 17), receiving standard chow; ADE (n = 17), given adenine in the chow at 0.7% for 1 wk and 0.5% for 2 wk; and ADE + pyrrolidine dithiocarbamate (PDTC; n = 14), receiving adenine as above and the NF-κB inhibitor PDTC (120 mg·kg⁻¹·day⁻¹ in the drinking water). After 3 wk, widespread crystal deposition was seen in tubular lumina and in the renal interstitium, along with granuloma formation, collagen accumulation, intense tubulointerstitial proliferation, and increased interstitial expression of inflammatory mediators. Part of the crystals were segregated from tubular lumina by a newly formed cell layer and, at more advanced stages, appeared to be extruded to the interstitium. p65 nuclear translocation and IKK-α increased abundance indicated activation of the NF-κB system. PDTC treatment prevented p65 migration and normalized IKK-α, limited crystal shift to the interstitium, and strongly attenuated interstitial fibrosis/inflammation. These findings indicate that the complex inflammatory phenomena associated with this model depend, at least in part, on NF-κB activation, and suggest that the NF-κB system may become a therapeutic target in the treatment of chronic kidney disease.
authors: Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo São Paulo, Brazil.
authors: Cristiene
authors: C
authors: Okabe
authors: Raquel Lerner
authors: RL
authors: Borges
authors: Danilo Candido
authors: DC
authors: de Almeida
authors: Camilla
authors: C
authors: Fanelli
authors: Grasiela Pedreira
authors: GP
authors: Barlette
authors: Flavia Gomes
authors: FG
authors: Machado
authors: Simone Costa Alarcon
authors: SC
authors: Arias
authors: Denise Maria Avancini Costa
authors: DM
authors: Malheiros
authors: Niels Olsen Saraiva
authors: NO
authors: Camara
authors: Roberto
authors: R
authors: Zatz
authors: Clarice Kazue
authors: CK
authors: Fujihara
mesh_terms: D000225:Adenine / Q000009:adverse effects / Q000031:analogs & derivatives*; D000818:Animals; D004195:Disease Models, Animal; D005355:Fibrosis; D006099:Granuloma / Q000209:etiology; D018836:Inflammation Mediators / Q000378:metabolism* / Q000502:physiology; D007668:Kidney / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009395:Nephritis, Interstitial / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D009400:Nephrosclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D011759:Pyrrolidines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013859:Thiocarbamates / Q000627:therapeutic use*
chemical_list: D018836:Inflammation Mediators; D016328:NF-kappa B; D011759:Pyrrolidines; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; C002993:2,8-dihydroxyadenine; D000225:Adenine
keywords: NF-κB; adenine; chronic kidney disease; granulomas; innate immunity