NF-kappa B activation mediates crystal translocation and interstitial inflammation in adenine overload nephropathy

Author(s):Show less -

Okabe, Cristiene ^[1] ; Borges, Raquel Lerner ^[1] ; de Almeida, Danilo Candido ^[2] ; Fanelli, Camilla ^[1] ; Barlette, Grasiela Pedreira ^[1] ; Machado, Flavia Gomes ^[1] ; Alarcon Arias, Simone Costa ^[1] ; Avancini Costa Malheiros, Denise Maria ^[1] ; Saraiva Camara, Niels Olsen ^[2] ; Zatz, Roberto ^[1] ; Fujihara, Clarice Kazue ^[1]

Affiliation

^[1] Univ Sao Paulo, Fac Med, Dept Clin Med, Div Renal, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Inst Biomed Sci, Lab Transplantat Immunobiol, Sao Paulo - Brazil

• Document type: Journal article
• Source: AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY; v. 305, n. 2, p. F155-F163, JUL 2013.
• Web of Science Citations: 13

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-kappa B 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-kappa B 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-alpha increased abundance indicated activation of the NF-kappa B system. PDTC treatment prevented p65 migration and normalized IKK-alpha, 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-kappa B activation, and suggest that the NF-kappa B system may become a therapeutic target in the treatment of chronic kidney disease. (AU)

• FAPESP's process: 12/08775-9 - Experimental chronic kidney disease by dietary adenine overload: initial tubular injury, mechanism of granuloma formation and prevention of fibrosis
• Grantee: Clarice Kazue Fujihara
• Support Opportunities: Regular Research Grants
• FAPESP's process: 11/10943-4 - The effects of anti-angiogenesis agent, malato de sunitinib (Sutent), administration in the 5/6 renal ablation (Nx) model
• Grantee: Clarice Kazue Fujihara
• Support Opportunities: Regular Research Grants