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) 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.

β-Arrestins Negatively Regulate the Toll Pathway in Shrimp by Preventing Dorsal Translocation and Inhibiting Dorsal Transcriptional Activity

“…MAPK signaling has been implicated in stress and immunity in evolutionarily diverse species (45). The relationship between MAPK and Toll signaling still needs to be studied in invertebrates.…”

“…␤-Arrestins were initially identified as mediators of GPCR desensitization and endocytosis (45). Nowadays, they are acknowledged to have signaling functions in a wide variety of signaling pathways and modes of regulation, including the Hedgehog, Wnt, Notch, and TGF␤ pathways (46).…”

Gain-of-function Mutations in Transient Receptor Potential C6 (TRPC6) Activate Extracellular Signal-regulated Kinases 1/2 (ERK1/2)

“…ERK phosphorylation, and thereby activation, is increased in glomeruli and podocytes in response to angiotensin II infusion (49 -52), salt-sensitive hypertension (53), puromycin aminoglycoside nephropathy (54 -58), passive Heymann nephritis (59,60), rapidly progressive glomerulonephritis (61)(62)(63)(64), and diabetic nephropathy (65)(66)(67). Phospho-ERK levels in mesangial cells have been correlated with glomerular damage in IgA nephropathy (68). In podocytes, ERK has been implicated in mediating actin reorganization, cell migration, and proliferation (61) and in acting as a both proapoptotic (56, 69 -71) and antiapoptotic/prosurvival (58,60,(72)(73)(74) signal.…”

Knockdown of Cxcl10 Inhibits Mesangial Cell Proliferation in Murine Habu Nephritis Via ERK Signaling

“…MesPGN is known to be an autoimmune inflammatory disease, and it is well-defined by an increased cell number and extracellular matrix in the glomerular mesangium [3, 4]. Pathophysiological roles of chemokines and their cognate receptors have shed light on the detailed molecular mechanisms of glomerulonephritis.…”