Systemic Lupus Erythematosus Plasma Pathologically Upregulates Endothelin Receptor A Expression in Renal Cortical Endothelial Cells

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Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disorder that disproportionately affects women compared to men (9:1). Individuals with an SLE diagnosis have higher risks of developing cardiovascular disease (CVD) than non-SLE counterparts despite similar preventative therapeutics. Interestingly, 40-60% of SLE patients develop renal inflammation and/or injury (lupus nephritis) within the first 5 years of diagnosis. Endothelin-1 (ET-1), a potent vasoconstrictor, is shown to be elevated in lupus nephritis patients' plasma and urine. ET-1 has two cognate receptors: ETAR and ETBR. ETAR activation is shown to induce pro-inflammatory signaling and vasoconstriction, while ETBR acts juxtaposing to ETAR activation. Endothelial cells (ECs), the primary producer of ET-1, have been shown to upregulate ETAR expression in multiple renal pathologies including podocyte injury, focal segmental glomerulosclerosis (FSGS), and chronic kidney disease. However, no studies have explored whether renal injury in SLE leads to pathological upregulation of endothelial ETAR expression. We hypothesized that renal ECs pathologically upregulate ETAR expression in SLE contributing to renal inflammation and injury. From a cohort of recruited non-SLE control and SLE human subjects we observed an increase in plasma autoantibodies against ETAR in SLE that positively correlated with endothelial activation marker VCAM-1 (r=0.4315; p=0.0218). To study the effect of SLE plasma on ECs, we isolated primary human renal cortical ECs from transplant patient kidneys and subjected them to normotensive (5%) and hypertensive (10%) stretch at 1Hz for 48 hours in the presence of healthy control (n=6) versus SLE (n=6) serum. After 48 hours of stretch, mRNA analysis via RT-PCR showed trending decrease in Ednrb in cells treated with SLE serum and no change in Ednra mRNA expression at 5% stretch. Interestingly, protein analysis showed a trending increase in ETAR expression in SLE treated cells compared to healthy controls at 5% stretch (p=0.1320), that was significant when exposed to 10% stretch (p=0.0212). Indicating that endothelial mechanical forces and SLE have a compounding role in the pathological upregulation of endothelial ETAR. To confirm our findings in vivo, we utilized a murine model of SLE-like CVD (R848 treated B6.Nba2) shown to develop severe renal injury and cardiac dysfunction. Immunofluorescent staining of the kidneys at terminal timepoint demonstrated a strong colocalization of CD31 + ECs and ETAR expression. Moreover, when primary B6.Nba2 renal ECs were exposed to 5%,10%, and 15% mechanical stretch significant upregulation of ETAR occurred in a stretch dependent manner (p=0.0098). The pathological upregulation of endothelial ETAR in SLE warrants further exploration of the role of the endothelin system in renal pathologies in SLE and endothelial inflammation. VA BLRD IK2BX005605, DCI PTRF 2023-10, T32GM132055, R25GM113278, T32AR050958, T32GM152386 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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