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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.

SUBMITTER: Tamouza H

PROVIDER: S-EPMC5177564 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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The IgA1 immune complex-mediated activation of the MAPK/ERK kinase pathway in mesangial cells is associated with glomerular damage in IgA nephropathy.

Tamouza Houda H Chemouny Jonathan M JM Raskova Kafkova Leona L Berthelot Laureline L Flamant Martin M Demion Marie M Mesnard Laurent L Paubelle Etienne E Walker Francine F Julian Bruce A BA Tissandié Emilie E Tiwari Meetu K MK Camara Niels O S NO Vrtovsnik François F Benhamou Marc M Novak Jan J Monteiro Renato C RC Moura Ivan C IC

Kidney international 20120905 12

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 elevate ...[more]

PMID: 22951891

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Project description:IntroductionGalactose-deficient IgA1 (Gd-IgA1) is a critical pathogenic factor for IgA nephropathy (IgAN), but its value as a disease-specific biomarker remains controversial. We aimed to clarify the clinical significance of Gd-IgA1 in patients with IgAN.MethodsWe retrospectively reviewed 111 patients who were diagnosed with IgAN based on the findings of renal biopsies (RB) at Showa University Hospital since 2007. Serum Gd-IgA1 (s-Gd-IgA1) at the time of RB was compared among 111 IgAN patients, 18 Henoch-Schönlein purpura nephritis (HSPN) patients, 29 lupus nephritis (LN) patients, 28 ANCA-associated vasculitis (AAV) patients, and 13 minimal change disease (MCD) patients using ELISA with an anti-human Gd-IgA1-specific monoclonal antibody (KM55). We also immunohistochemically stained paraffin-embedded sections for mesangial Gd-IgA1 (m-Gd-IgA1) deposition using KM55.ResultsAlthough levels of s-Gd-IgA1 were comparable among IgAN and HSPN, s-Gd-IgA1 levels were significantly elevated in patients with IgAN compared with LN, AAV and MCD (IgAN vs. HSPN, LN, AAV, and MCD: 16.2 ± 9.1 vs. 14.2 ± 10.8, p = 0.263; 12.7 ± 9.4, p = 0.008; 13.1 ± 7.3, p = 0.059; and 8.2 ± 4.8 μg/mL, p<0.001, respectively). Mesangial-Gd-IgA1 deposition was specifically detected in IgAN or HSPN. The increase in s-Gd-IgA1 significantly correlated with m-Gd-IgA1 positivity in patients with IgAN, and s-Gd-IgA1 elevation and m-Gd-IgA1 deposition were evident in patients with histopathologically advanced IgAN. Moreover, s-Gd-IgA1 levels were significantly higher in IgAN patients with glomerular sclerosis and tubulo-interstitial lesions. Mesangial-Gd-IgA1 intensity negatively correlated with eGFR in IgAN. Multivariate analysis selected s-Gd-IgA1 elevation as a significant risk factor for a 30%-reduction in eGFR in IgAN (HR, 1.37; 95% CI, 1.02-1.89; p = 0.038).ConclusionsAlthough IgAN and HSPN remain difficult to differentiate, s-Gd-IgA1 elevation and m-Gd-IgA1 deposition are reliable diagnostic factors that reflect IgAN severity. Serum-Gd-IgA1 could serve as a predictor of renal outcomes in IgAN. Thus, Gd-IgA1 could be significant biomarker for patients with IgAN.

Project description:Background: Aberrant O-glycosylation of IgA1 plays an important role in IgA nephropathy pathogenesis. Previous proteomic studies analyzed O-glycans of the circulating IgA1 hinge region and found that the N-acetylgalactosamine (GalNAc) and galactose numbers in the hinge region of IgA1 of patients with IgA nephropathy were lower than those in healthy participants. However, the diagnostic performance of the O-glycosylation traits in the hinge region of plasma IgA1 for IgA nephropathy remains unelucidated. The present study aimed to determine the difference in plasma IgA1 hinge region O-glycoforms among IgA nephropathy, non-IgA nephropathy disease controls, and healthy participants, and to further evaluate the diagnostic performance of plasma IgA1 glycosylation traits. Methods: Sixty-two patients with biopsy-proven primary IgA nephropathy, 30 age- and sex-matched non-IgA nephropathy disease controls (10 patients with membranous nephropathy, 10 with focal segmental glomerulosclerosis, and 10 with minimal change disease), and 30 healthy participants were prospectively recruited. Plasma galactose deficient-IgA1 levels were measured using a KM55 kit. Plasma IgA was extracted using IgA immunoaffinity beads. After de-N-glycosylation, reduction, alkylation, trypsin digestion, and O-glycopeptide enrichment via hydrophilic interaction liquid chromatography, liquid chromatography tandem mass spectrometry (LC-MS/MS) was applied to analyze the IgA1 O-glycosylation patterns and we derived the plasma IgA1 O-glycosylation traits. Results: Plasma IgA1 O-glycosylation patterns were significantly changed in IgA nephropathy patients compared to those with non-IgA nephropathy disease controls and healthy participants. The GalNAc number was lowest in IgA nephropathy patients. In addition, a similar result was observed for the galactose number in the IgA1 hinge region. These values showed moderate potential for discriminating between IgA nephropathy and the controls. When these values were combined, the area under the curve increased compared to when they were considered individually. When further adding a clinical indicator, the area under the curve of the GalNAc-galactose-IgA panel exceed 0.9 in discriminating IgA nephropathy from the controls. Conclusion: The amount of GalNAc and galactose in plasma IgA1 hinge region identified by glycoproteomics could be used as a diagnostic biomarker for IgA nephropathy. The panel containing GalNAc, galactose, and circulating IgA displayed excellent diagnostic performance and is promising for practical clinical applications.

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The IgA1 immune complex-mediated activation of the MAPK/ERK kinase pathway in mesangial cells is associated with glomerular damage in IgA nephropathy.

Publications

The IgA1 immune complex-mediated activation of the MAPK/ERK kinase pathway in mesangial cells is associated with glomerular damage in IgA nephropathy.

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