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.