A Uromodulin Mutation Drives Autoimmunity and Kidney Mononuclear Phagocyte Endoplasmic Reticulum Stress.

ABSTRACT: We identified a family with a UMOD gene mutation (C106F) resulting in glomerular inflammation and complement deposition. To determine if the observed phenotype is due to immune system activation by mutant uromodulin, a mouse strain with a homologous cysteine to phenylalanine mutation (C105F) in the UMOD gene was generated using CRISPR-Cas9 gene editing and the effect of this mutation on mononuclear phagocytic cells was examined. Mutant mice developed high levels of intracellular and secreted aggregated uromodulin, resulting in anti-uromodulin antibodies and circulating uromodulin containing immune complexes with glomerular deposition and kidney fibrosis with aging. F4/80⁺ and CD11c⁺ kidney cells phagocytize uromodulin. Differential gene expression analysis by RNA sequ

SUBMITTER: Plotkin M 

PROVIDER: S-EPMC7722528 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature