Sex diversity in proximal tubule and endothelial gene expression in mice with ischemic acute kidney injury

Female sex protects against development of acute kidney injury (AKI). While sex hor-mones may be involved in protection, the role of differential gene expression is un-known. We conducted gene profiling in male and female mice with or without kidney ischemia-reperfusion injury (IRI). Mice underwent bilateral renal pedicle clamping (30 min), and tissues were collected 24 h after reperfusion. RNA-sequencing (RNA-Seq) was per-formed on proximal tubules (PTs) and kidney endothelial cells. Female mice were resistant to ischemic injury compared with males, determined by plasma creatinine and neutrophil gelatinase-associated lipocalin (NGAL), histologic scores, neutrophil infiltration, and extent of apoptosis. Sham mice had sex-specific gene disparities in PT and endothelium, and male mice showed profound gene dysregulation with ischemia-reperfusion compared with fe-males. After ischemia PTs from females exhibited smaller increases compared with males in injury-associated genes lipocalin-2 (Lcn2), hepatitis A virus cellular receptor 1 (Havcr1), and keratin 18 (Krt18), and no up-regulation of SRY-Box transcription factor 9 (Sox9) or keratin 20 (Krt20). Endothelial up-regulation of adhesion molecules and cytokines/chemokines oc-curred in males, but not females. Up-regulated genes in male ischemic PTs were linked to tumor necrosis factor (TNF) and Toll-like receptor (TLR) pathways, while female ischemic PTs showed up-regulated genes in pathways related to transport. The data highlight sex-specific gene expression differences in male and female PTs and endothelium before and after is-chemic injury that may underlie disparities in susceptibility to AKI.