3 years ago

ABIN1 determines severity of glomerulonephritis via activation of intrinsic glomerular inflammation

Transcription factor NF-κB regulates expression of numerous genes that control inflammation and is activated in glomerular cells in glomerulonephritis (GN). We previously identified genetic variants for a NF-κB regulatory, ubiquitin binding protein ABIN1 as risk factors for GN in systemic autoimmunity. The goal here was to define glomerular inflammatory events controlled by ABIN1 function in GN. Nephrotoxic serum nephritis was induced in wild-type (WT) and ubiquitin binding deficient ABIN1[D485N] mice; and renal pathophysiology and glomerular inflammatory phenotypes were assessed. Proteinuria was also measured in ABIN1[D485N] mice transplanted with WT mouse bone marrow. Inflammatory activation of ABIN1[D472N] (D485N homolog) cultured human-derived podocytes and interaction with primary human neutrophils were also assessed. Disruption of ABIN1 function exacerbated proteinuria, podocyte injury, glomerular NF-κB activity, glomerular expression of inflammatory mediators, and glomerular recruitment and retention of neutrophils in antibody-mediated nephritis. Transplantation of WT bone marrow did not prevent the increased proteinuria in ABIN1[D845N] mice. TNF-stimulated enhanced expression and secretion of NF-κB-targeted pro-inflammatory mediators in ABIN1[D472N] cultured podocytes, compared with WT cells. Supernatants from ABIN1[D472N] podocytes accelerated chemotaxis of human neutrophils and ABIN1[D472N] podocytes displayed a greater susceptibility to an injurious morphology induced by neutrophil granule contents. These studies define a novel role for ABIN1 dysfunction and NF-κB in mediating glomerulonephritis through proinflammatory activation of podocytes.

Publisher URL: www.sciencedirect.com/science

DOI: S0002944017303280

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