title: The IgA1 immune complex-mediated activation of the MAPK/ERK kinase pathway in mesangial cells is associated with glomerular damage in IgA nephropathy.
abstract: IgA nephropathy (IgAN), the most common primary glomerulonephritis worldwide, has significant morbidity and mortality as 20-40% of patients progress to end-stage renal disease within 20 years of onset. In order to gain insight into the molecular mechanisms involved in the progression of IgAN, we systematically evaluated renal biopsies from such patients. This showed that the MAPK/ERK signaling pathway was activated in the mesangium of patients presenting with over 1 g/day proteinuria and elevated blood pressure, but absent in biopsy specimens of patients with IgAN and modest proteinuria (<1 g/day). ERK activation was not associated with elevated galactose-deficient IgA1 or IgG specific for galactose-deficient IgA1 in the serum. In human mesangial cells in vitro, ERK activation through mesangial IgA1 receptor (CD71) controlled pro-inflammatory cytokine secretion and was induced by large-molecular-mass IgA1-containing circulating immune complexes purified from patient sera. Moreover, IgA1-dependent ERK activation required renin-angiotensin system as its blockade was efficient in reducing proteinuria in those patients exhibiting substantial mesangial activation of ERK. Thus, ERK activation alters mesangial cell-podocyte crosstalk, leading to renal dysfunction in IgAN. Assessment of MAPK/ERK activation in diagnostic renal biopsies may predict the therapeutic efficacy of renin-angiotensin system blockers in IgAN.
authors.affiliation: INSERM U699, Paris, France.
authors.forename: Houda
authors.initials: H
authors.lastname: Tamouza
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Chemouny
authors.forename: Leona
authors.initials: L
authors.lastname: Raskova Kafkova
authors.forename: Laureline
authors.initials: L
authors.lastname: Berthelot
authors.forename: Martin
authors.initials: M
authors.lastname: Flamant
authors.forename: Marie
authors.initials: M
authors.lastname: Demion
authors.forename: Laurent
authors.initials: L
authors.lastname: Mesnard
authors.forename: Etienne
authors.initials: E
authors.lastname: Paubelle
authors.forename: Francine
authors.initials: F
authors.lastname: Walker
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Julian
authors.forename: Emilie
authors.initials: E
authors.lastname: Tissandié
authors.forename: Meetu K
authors.initials: MK
authors.lastname: Tiwari
authors.forename: Niels O S
authors.initials: NO
authors.lastname: Camara
authors.forename: François
authors.initials: F
authors.lastname: Vrtovsnik
authors.forename: Marc
authors.initials: M
authors.lastname: Benhamou
authors.forename: Jan
authors.initials: J
authors.lastname: Novak
authors.forename: Renato C
authors.initials: RC
authors.lastname: Monteiro
authors.forename: Ivan C
authors.initials: IC
authors.lastname: Moura
mesh_terms: D000328:Adult; D000368:Aged; D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000936:Antigen-Antibody Complex; D015703:Antigens, CD / Q000378:metabolism; D001706:Biopsy; D001794:Blood Pressure; D002118:Calcium / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D005922:Glomerulonephritis, IGA / Q000201:enzymology / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D008875:Middle Aged; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D050199:Podocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D011507:Proteinuria / Q000201:enzymology / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism; D012084:Renin-Angiotensin System; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D055815:Young Adult
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000936:Antigen-Antibody Complex; D015703:Antigens, CD; C068126:CD71 antigen; C508600:IL6 protein, human; D007070:Immunoglobulin A; D018836:Inflammation Mediators; D015850:Interleukin-6; D011990:Receptors, Transferrin; D000804:Angiotensin II; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium