ELF3 links kidney function GWAS loci to maladaptive epithelial inflammation.

Abstract

Genome-wide association studies (GWAS) have uncovered over a thousand loci associated with kidney function, but the effector genes and mechanisms remain largely unknown. Here, we demonstrate that <i>ELF3</i> is the effector gene at a kidney function GWAS locus and acts as an epithelial proinflammatory amplifier of the reprogramming of injured proximal tubules (iPTs). E74-like factor 3 (ELF3) expression is induced in iPTs in both mouse models and human chronic kidney disease (CKD), where it defines transitional epithelial states enriched for inflammatory gene programs and surrounded by leukocyte infiltrates. Conditional deletion of <i>Elf3</i> in mice after injury reduced iPT accumulation, cytokine production, and immune cell recruitment. Mechanistically, ELF3 directly bound and activated components of the noncanonical nuclear factor κB (NF-κB) pathway (<i>Nf</i>κ<i>b2</i>, <i>Map3k14</i>, and <i>Il6r</i>) and was required for NFκB2 nuclear translocation and cytokine induction. Spatial transcriptomics and immunofluorescence of human CKD kidneys confirmed that ELF3 expression correlates with epithelial inflammation, disease progression, and loss of kidney function. Together, these findings establish <i>ELF3</i> as a genetically validated effector gene that drives inflammatory reprogramming in iPTs, nominating it as a therapeutic target to blunt maladaptive inflammation in CKD.