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Spontaneous activation of the NF-B signaling pathway in isolated normal glomeruli

¹Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan; and ²Organ Transplantation Unit, 1^stAffiliated Hospital, China Medical University, Shenyang, China

Submitted 21 December 2005 ; accepted in final form 8 May 2006

In this report, we describe that NF-B is spontaneously activated in isolated, normal glomeruli. Ex vivo incubation of isolated rat glomeruli triggered expression of a NF-B-dependent gene, monocyte chemoattractant protein-1 (MCP-1), in parallel with downregulation of IB and IB proteins and activation of the p65 NF-B subunit. The induction of MCP-1 was also observed in mesangial cells coincubated with isolated glomeruli or exposed to media conditioned by isolated glomeruli (GCM), which was abrogated by inhibition of NF-B. The activation of NF-B by glomerulus-derived factors was confirmed using reporter mesangial cells that produce secreted alkaline phosphatase (SEAP) under the control of the B enhancer element. When the reporter cells were adoptively transferred into normal glomeruli, expression of SEAP mRNA and activity of SEAP were also upregulated in the explanted glomeruli. The molecular weight of factors responsible for activation of NF-B was >50 kDa, and TNF- was identified as one of glomerulus-derived activators. To examine upstream events involved, we focused on MAP kinases that are spontaneously activated in explanted glomeruli. Selective suppression of ERK or p38 MAP kinase significantly attenuated activation of NF-B in mesangial cells triggered by coculture with isolated glomeruli. Interestingly, the suppressive effects by MAP kinase inhibitors were not observed in mesangial cells treated with GCM. These data suggested that NF-B was spontaneously activated in explanted glomeruli via autocrine/paracrine factors including TNF- and that the production of NF-B activators by glomeruli was, at least in part, through MAP kinase pathways.

isolated glomerulus; mesangial cell; TNF-; MAP kinase

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