Sex-dependent Regulation of Endothelial Antigen Processing and Presentation and Activation in the Development of Salt-sensitive Hypertension

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Hypertension (HTN) is the leading cause of morbidity and mortality for stroke, myocardial infarction, heart failure and chronic kidney disease. Additionally, according to new HTN guidelines, approximately 50% of adults worldwide have HTN, with 20% of these adults are non-responsive to current anti-hypertensive therapeutics. Over the last two decades, immune cells and inflammation have been demonstrated to be critical mediators of HTN and renal injury. It has been demonstrated in vitro that renal endothelial cells (ECs) express and regulate classical immunological proteins such as major histocompatibility complex (MHC) I and II in a sex-dependent manner. However, the in vivo sex-dependent regulation of renal endothelial MHC I and II has yet to elucidated. We hypothesized that renal endothelial antigen processing and presentation mechanisms would be upregulated in males compared to females in salt-sensitive HTN (SSHTN). Male and female C57Bl/6J (n=6/group) mice were subjected to the N(G)-Nitro-L-arginine-methyl ester (L-NAME) high salt feeding regimen. Mice were subjected to L-NAME (0.5 mg/mL) for 2 weeks in their drinking water. After the 2 weeks, mice were given free access to normal food and water. Mice were then randomized to receive a 4.0% high salt or 0.4% normal salt diet for 4 weeks. After the 4 weeks, mice were euthanized and both kidneys and plasma were collected. One kidney was fixed and processed for histological analysis. The primary renal endothelial were isolated by CD31 + magnetic bead isolation from the other kidney and processed for RNA sequencing. Immunofluorescence microscopy yielded the presence of MHC I and II in both male and female renal ECs independent of salt diet. RNA sequencing was performed to determine potential mechanisms of sex-dependent regulation. In SSHTN, there was a total of 12,102 genes that were similar, however 351 genes in males and 356 genes in females were differentially expressed. Next, we investigated antigen processing and presentation associated genes in a sex-dependent manner and found males upregulated antigen presentation ( H2-K-1, H-Ab1, B2m, H2-T22, and H2-T23; padj<0.05), antigen processing ( Tapbp, Tap1, Tap2, Psmb4, Psmb6, and Psmb8; padj<0.05), and adhesion molecules ( Icam1, Vcam1, and Esam; padj<0.05). In comparison, females demonstrated no significant change in any antigen processing and presentation associated genes. Furthermore, gene ontology (GO) enrichment analysis demonstrated female ECs have a significant reduction in MHC protein complex, antigen binding, beta-2-microgloublin, peptide antigen binding compared to male ECs in salt-sensitive HTN. Analysis of plasma for soluble vascular adhesion molecule-1 (sVCAM-1) revealed males had a profound upregulation of sVCAM-1 while females exhibited no change in response to SSHTN (<0.0001). Therefore, our data demonstrates that renal EC antigen processing and presentation genes and endothelial cell activation are regulated in a sex-dependent manner in SSHTN. Our findings may provide novel therapeutic strategies to target renal endothelial inflammation and activation in a sex-dependent manner in SSHTN. VA BLRD 1IK2BX005605, DCI PTRF 2023-10, T32AR050958, T32GM152386, 5R25GM113278 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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