Elucidating Endothelin System and Piezo1 Endothelial Cell Crosstalk in Systemic Lupus Erythematosus

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Systemic lupus erythematosus (SLE) is characterized by the production of autoantibodies that results in systemic IgG deposition in multiple organs and in the vasculature. In fact, SLE patients have high incidence of vascular complications, including hypertension, vascular inflammation, and endothelial dysfunction. While the high risk of cardiovascular mortality in SLE patients is known, the cause of vascular complications remains to be elucidated. The vascular pathology of SLE involves endothelial activation and dysfunction, as well as the dysregulation of the endothelin system. Endothelin-1 (ET-1), a potent vasoconstrictor, and its two G couple protein receptors (ET A R and ET B R) are implicated in multiple diseases, including SLE. Importantly, biological activity of ET A R autoantibodies (ET A R-AAs) have been demonstrated in studies of systemic sclerosis, cystic fibrosis, and pulmonary hypertension. Beyond the ET system, mechanosensitive ion channel Piezo1 is highly expressed in endothelial cells and has recently been linked to lupus nephritis development. However, no studies have investigated the ET system and Piezo1 in tandem in health or SLE disease states. Here, we hypothesize that ET A R and Piezo1 crosstalk promotes endothelial cell dysfunction in SLE. To investigate this, we used patient samples from recruited non-SLE and SLE human subjects, which were analyzed for clinical characteristics including plasma ET A R autoantibodies and soluble vascular adhesion molecule-1 (sVCAM-1). Furthermore, we isolated primary human cortical endothelial cells (HREC) from transplant kidneys and incubated them for 24hrs with isolated IgG from our non-SLE and SLE subjects with and without ET A R and Piezo1 inhibition by BQ123 and GSMTx-4, respectively. We found SLE subjects had a profound increase in plasma ET A R-AAs compared to non-SLE (p<0.0001). Further, plasma ET A R-AAs positively associated with sVCAM-1 (r=0.4288; p=0.0114), indicative of endothelial dysfunction. In vitro, primary HRECs incubated with SLE IgG resulted in the reduction of both ET A R (p=0.0087) and Piezo1 (p=0.0266) protein expression relative to non-SLE IgG controls. This data indicates a potential novel pathophysiological crosstalk of ET A R and Piezo1 in SLE. Interestingly, this reduction of ET A R and Piezo1 expression with stimulated with SLE IgG was prevented by BQ123 and GSMTx-4 co-treatment. Specifically, there was preservation of both ET A R expression with SLE IgG + GSMTx-4 (p=0.2657) and Piezo1 expression with SLE IgG + BQ123 co-treatment (p=0.5799), indicating the possibility of novel ET A R/Piezo1 endothelial cell crosstalk in SLE. Piezo1. Overall, this data suggests a potential novel endothelial signaling mechanism of ETAR-Piezo1 in the development of endothelial dysfunction in response to SLE autoantibodies. 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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