PMID- 11096048
OWN - NLM
STAT- MEDLINE
DCOM- 20010111
LR  - 20220317
IS  - 1523-6838 (Electronic)
IS  - 0272-6386 (Linking)
VI  - 36
IP  - 6
DP  - 2000 Dec
TI  - Protein traffic activates NF-kB gene signaling and promotes MCP-1-dependent 
      interstitial inflammation.
PG  - 1226-41
AB  - 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.
FAU - Donadelli, R
AU  - Donadelli R
AD  - Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
FAU - Abbate, M
AU  - Abbate M
FAU - Zanchi, C
AU  - Zanchi C
FAU - Corna, D
AU  - Corna D
FAU - Tomasoni, S
AU  - Tomasoni S
FAU - Benigni, A
AU  - Benigni A
FAU - Remuzzi, G
AU  - Remuzzi G
FAU - Zoja, C
AU  - Zoja C
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Am J Kidney Dis
JT  - American journal of kidney diseases : the official journal of the National Kidney 
      Foundation
JID - 8110075
RN  - 0 (Angiotensin-Converting Enzyme Inhibitors)
RN  - 0 (Chemokine CCL2)
RN  - 0 (NF-kappa B)
RN  - 0 (RNA, Messenger)
SB  - IM
MH  - Angiotensin-Converting Enzyme Inhibitors/*pharmacology
MH  - Chemokine CCL2
MH  - Gene Expression Regulation/drug effects
MH  - Kidney Diseases/*drug therapy
MH  - NF-kappa B
MH  - Protein Transport/drug effects
MH  - Proteinuria/*drug therapy
MH  - RNA, Messenger
EDAT- 2000/11/30 11:00
MHDA- 2001/02/28 10:01
CRDT- 2000/11/30 11:00
PHST- 2000/11/30 11:00 [pubmed]
PHST- 2001/02/28 10:01 [medline]
PHST- 2000/11/30 11:00 [entrez]
AID - S0272-6386(00)46353-5 [pii]
AID - 10.1053/ajkd.2000.19838 [doi]
PST - ppublish
SO  - Am J Kidney Dis. 2000 Dec;36(6):1226-41. doi: 10.1053/ajkd.2000.19838.