Protein traffic activates NF-kB gene signaling and promotes MCP-1-dependent interstitial inflammation.
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.
Donadelli
R
R
Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Abbate
M
M
Zanchi
C
C
Corna
D
D
Tomasoni
S
S
Benigni
A
A
Remuzzi
G
G
Zoja
C
C
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D018932:Chemokine CCL2; D005786:Gene Expression Regulation / Q000187:drug effects; D007674:Kidney Diseases / Q000188:drug therapy*; D016328:NF-kappa B; D021381:Protein Transport / Q000187:drug effects; D011507:Proteinuria / Q000188:drug therapy*; D012333:RNA, Messenger
D000806:Angiotensin-Converting Enzyme Inhibitors; D018932:Chemokine CCL2; D016328:NF-kappa B; D012333:RNA, Messenger