Interferon-regulated genetic programs and JAK/STAT pathway activate the intronic promoter of the short ACE2 isoform in renal proximal tubules

Recently, a short, interferon-inducible isoform of Angiotensin-Converting Enzyme 2 (ACE2), dACE2 was identified. ACE2 is a SARS-Cov-2 receptor and changes in its renal expression have been linked to several human nephropathies. These changes were never analyzed in context ofdACE2, as its expression was not investigated in the kidney. We used Human Primary Proximal Tubule (HPPT) cells to show genome-wide gene expression patterns after cytokine stimulation, with emphasis on theACE2/dACE2locus. Putative regulatory elements controllingdACE2expression were identified using ChIP-seq and RNA-seq. qRT-PCR differentiating betweenACE2anddACE2revealed 300- and 600-fold upregulation ofdACE2by IFNα and IFNβ, respectively, while full lengthACE2expression was almost unchanged. JAK inhibitor ruxolitinib ablatedSTAT1anddACE2expression after interferon treatment. Finally, with RNA-seq, we identified a set of genes, largely immune-related, induced by cytokine treatment. These gene expression profiles provide new insights into cytokine response of proximal tubule cells.