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Am J Pathol. 2017 Dec;187(12):2799-2810. doi: 10.1016/j.ajpath.2017.08.018. Epub 2017 Sep 19.

ABIN1 Determines Severity of Glomerulonephritis via Activation of Intrinsic Glomerular Inflammation.

Author information

1
Department of Medicine University of Louisville, Louisville, Kentucky.
2
Department of Medicine University of Louisville, Louisville, Kentucky; Robley Rex VA Medical Center, Louisville, Kentucky.
3
Department of Internal Medicine-Nephrology, University of Michigan, Ann Arbor, Michigan.
4
Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky.
5
Arthritis and Clinical Immunology Program and Clinical Pharmacology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma.
6
Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.
7
Department of Medicine University of Louisville, Louisville, Kentucky; Department of Internal Medicine-Nephrology, University of Michigan, Ann Arbor, Michigan.
8
Department of Medicine University of Louisville, Louisville, Kentucky. Electronic address: david.powell@louisville.edu.

Abstract

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 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. Tumor necrosis factor-stimulated enhanced expression and secretion of NF-κB-targeted proinflammatory 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 injurious morphologic findings induced by neutrophil granule contents. These studies define a novel role for ABIN1 dysfunction and NF-κB in mediating GN through proinflammatory activation of podocytes.

PMID:
28935578
PMCID:
PMC5718094
DOI:
10.1016/j.ajpath.2017.08.018
[Indexed for MEDLINE]
Free PMC Article

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