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

Abstract

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and has significant morbidity and mortality as 20–40% of patients progress to end-stage renal disease (ESRD) within 20 years after disease onset. We aimed to gain insight into the molecular mechanisms involved in IgAN progression. A systematic evaluation of renal biopsy specimens from IgAN patients revealed that the MAPK/ERK signaling pathway was activated in mesangial areas of patients presenting with >1 g/day proteinuria and elevated blood pressure, but was absent in biopsy specimens from IgAN patients with modest proteinuria (<1 g/day). ERK activation was not associated with elevated serum levels of galactose (Gal)-deficient IgA1 or IgG specific for Gal-deficient IgA1. In in vitro studies with human mesangial cells, ERK activation controlled pro-inflammatory cytokine secretion and was induced by patients’ large-molecular-mass IgA1-containing circulating immune complexes. Moreover, we show that IgA1-dependent MAPK/ERK activation required renin-angiotensin system (RAS) activity. Finally, RAS blockers were more efficient in reducing proteinuria in IgAN patients exhibiting substantial mesangial activation of MAPK/ERK. Together, these results suggest that MAPK/ERK activation alters the mesangial cell-podocyte cross-talk, leading to renal dysfunction in IgAN. Assessment of MAPK/ERK activation status in diagnostic renal biopsies could therefore serve as a biomarker to predict the efficacy of RAS blockers in IgAN.