Transcriptional and post-transcriptional alterations of IkappaBalpha in active minimal-change nephrotic syndrome.
Minimal-change nephrotic syndrome (MCNS) is a renal disease characterized by heavy glomerular proteinuria and increased production of cytokines by immune cells. Because of the central role of nuclear factor-kappaB (NF-kappaB) in the regulation of cytokine expression, its activity during the relapse and remission phases of steroid-sensitive MCNS was analyzed. During relapse, nuclear extracts from peripheral blood mononuclear cells displayed high levels of NF-kappaB DNA-binding activity, consisting primarily of p50/RelA (p65) complexes. NF-kappaB p65 and IkappaBalpha proteins were barely detected or not detected in cytosolic fractions during relapse, in contrast to remission. The lack of expression of IkappaBalpha protein was associated with downregulation of IkappaBalpha mRNA and increases in the levels of the mRNA encoding the proteasome alpha2 subunit proteolytic pathway. In addition, inhibition of proteasome activity induced cytosolic accumulation of phosphorylated IkappaBalpha and significant reductions in the NF-kappaB binding activity in nuclear extracts from peripheral blood mononuclear cells from patients experiencing relapses. These results suggest that alterations in the NF-kappaB/IkappaBalpha regulatory feedback loop may contribute to the immunologic abnormalities that occur in steroidsensitive MCNS.
Sahali
Djillali
D
Institut National de la Santé et de la Recherche Médicale Unit 99, Henri Mondor Hospital, Créteil, France.|Nephrology Service, Armand Trousseau Hospital, Paris, France.
Pawlak
André
A
Institut National de la Santé et de la Recherche Médicale Unit 99, Henri Mondor Hospital, Créteil, France.
Gouvello
Sabine LE
SL
Institut National de la Santé et de la Recherche Médicale Unit 99, Henri Mondor Hospital, Créteil, France.|Immunology-Biology Service, University of Paris XII, Créteil, France.
Lang
Philippe
P
Upress B JE 2129, Henri Mondor Hospital, Créteil, France.|Nephrology Service, Henri Mondor Hospital, Créteil, France.
Valanciuté
Asta
A
Institut National de la Santé et de la Recherche Médicale Unit 99, Henri Mondor Hospital, Créteil, France.
Remy
Philippe
P
Nephrology Service, Henri Mondor Hospital, Créteil, France.
Loirat
Chantal
C
Nephrology Service, Robert Debré Hospital, Paris, France.
Niaudet
Patrick
P
Nephrology Service, Necker Hospital for Sick Children, Assistance Publique des Hôpitaux de Paris, Paris, France.
Bensman
Albert
A
Upress B JE 2129, Henri Mondor Hospital, Créteil, France.|Nephrology Service, Armand Trousseau Hospital, Paris, France.
Guellaen
Georges
G
Institut National de la Santé et de la Recherche Médicale Unit 99, Henri Mondor Hospital, Créteil, France.
D000293:Adolescent; D000328:Adult; D002467:Cell Nucleus / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003546:Cysteine Endopeptidases / Q000502:physiology; D003593:Cytoplasm / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D009000:Monocytes / Q000378:metabolism; D009097:Multienzyme Complexes / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology; D009402:Nephrosis, Lipoid / Q000235:genetics / Q000378:metabolism*; D009404:Nephrotic Syndrome / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011499:Protein Processing, Post-Translational; D012008:Recurrence; D014158:Transcription, Genetic
D020672:I-kappa B Proteins; D009097:Multienzyme Complexes; D016328:NF-kappa B; D004247:DNA; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex