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Am J Kidney Dis. 2000 Dec;36(6):1226-41.

Protein traffic activates NF-kB gene signaling and promotes MCP-1-dependent interstitial inflammation.

Author information

1
Mario Negri Institute for Pharmacological Research, Bergamo, Italy.

Abstract

Mononuclear cells accumulate in the renal interstitium and contribute to renal injury in proteinuric nephropathies. Angiotensin-converting enzyme (ACE) inhibitors reduce protein trafficking and also lessen renal structural and functional damage. Many proinflammatory genes, including monocyte chemoattractant protein-1 (MCP-1), a chemoattractant for monocytes and T lymphocytes, are transcriptionally regulated by nuclear factor-kappa B (NF-kB). We aimed to study NF-kB activation and MCP-1 expression over time in two models of progressive proteinuric nephropathies (5/6 nephrectomy and passive Heymann nephritis [PHN]) and evaluate the effect of antiproteinuric therapy with an ACE inhibitor on these factors. In both models, increased urinary protein excretion over time was associated with a remarkable increase in NF-kB activity, which was almost completely suppressed by reducing proteinuria with lisinopril. NF-kB activation was paralleled by upregulation of MCP-1 messenger RNA and interstitial accumulation of ED-1-positive monocytes/macrophages and CD8-positive T cells. Lisinopril inhibited MCP-1 upregulation and limited interstitial inflammation. In a group of PHN rats with advanced disease and severe proteinuria, a dose of lisinopril high enough to inhibit renal ACE activity failed to reduce proteinuria and also did not limit NF-kB activation, which was sustained over time, along with MCP-1 gene overexpression and interstitial inflammation. These data suggest that NF-kB is activated in the presence of increased protein traffic, enhancing the nuclear transcription of the MCP-1 gene with potent chemotactic and inflammatory properties. This mechanism may help explain the long-term renal toxicity of filtered proteins.

PMID:
11096048
DOI:
10.1053/ajkd.2000.19838
[Indexed for MEDLINE]

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