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. (C) 2000 by the National Kidney Foundation, Inc.
| Original language | English |
|---|---|
| Pages (from-to) | 1226-1241 |
| Number of pages | 16 |
| Journal | American Journal of Kidney Diseases |
| Volume | 36 |
| Issue number | 6 |
| Publication status | Published - 2000 |
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Keywords
- Angiotensin-converting enzyme (ACE) inhibitor
- Interstitial inflammation
- Monocyte chemoattractant protein-1 (MCP-1)
- Nuclear factor kappa B (NF-kB) activation
- Proteinuria
ASJC Scopus subject areas
- Nephrology
Cite this
Protein traffic activates NF-kB gene signaling and promotes MCP-1-dependent interstitial inflammation. / Donadelli, Roberta; Abbate, Mauro; Zanchi, Cristina; Corna, Daniela; Tomasoni, Susanna; Benigni, Ariela; Remuzzi, Giuseppe; Zoja, Carla.
In: American Journal of Kidney Diseases, Vol. 36, No. 6, 2000, p. 1226-1241.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Protein traffic activates NF-kB gene signaling and promotes MCP-1-dependent interstitial inflammation
AU - Donadelli, Roberta
AU - Abbate, Mauro
AU - Zanchi, Cristina
AU - Corna, Daniela
AU - Tomasoni, Susanna
AU - Benigni, Ariela
AU - Remuzzi, Giuseppe
AU - Zoja, Carla
PY - 2000
Y1 - 2000
N2 - 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. (C) 2000 by the National Kidney Foundation, Inc.
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. (C) 2000 by the National Kidney Foundation, Inc.
KW - Angiotensin-converting enzyme (ACE) inhibitor
KW - Interstitial inflammation
KW - Monocyte chemoattractant protein-1 (MCP-1)
KW - Nuclear factor kappa B (NF-kB) activation
KW - Proteinuria
UR - http://www.scopus.com/inward/record.url?scp=0033653377&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033653377&partnerID=8YFLogxK
M3 - Article
C2 - 11096048
AN - SCOPUS:0033653377
VL - 36
SP - 1226
EP - 1241
JO - American Journal of Kidney Diseases
JF - American Journal of Kidney Diseases
SN - 0272-6386
IS - 6
ER -