Sex Differences of the Endothelin System in the Cardio-Renal Axis of a Lupus Prone Mouse Model

Abstract

Systemic Lupus Erythematosus (SLE) is the most common form of lupus autoimmunity. It is characterized by overactivation of toll-like receptor 7 (TLR7) and immune complex deposition in target organs including the kidney and vasculature. A lupus diagnosis disproportionately affects women at a rate of 9:1 compared to men. Clinically, patients present with heterogenous symptoms including chronic hypertension, heart failure, renal failure, vascular disease, and neuropathies. Despite a variety of clinical presentations of lupus, elevated endothelin-1 (ET-1) has been detected in both male and female lupus patients' plasma compared to healthy controls. However, the exact sex differences in ET-1 in the development of lupus and its associated cardiovascular complications remain unknown. Therefore, we hypothesized that acceleration of SLE through TLR7 activation promotes sex-dependent regulation of the ET system within the cardiorenal axis. To investigate this, female and male lupus-prone B6.Nba2 mice were treated with a TLR7/8 agonist (R848; 100ug/30ul) or acetone as a control topically twice a week for 4 weeks. After the R848 treatment, mice were followed for 12 more weeks until the 16-week terminal timepoint where the kidney and heart tissues were collected and tissue ET-1, endothelin receptor A (ETA) and endothelin receptor B (ETB) were analyzed by ELISA, RTqPCR, and immunoblotting. At the RNA level, cardiac Ednra expression trended towards upregulation in females, whereas males remained unchanged compared to their respective controls. At the protein level, both sexes tended to decrease ETA receptor levels. Renal Ednra expression trended towards downregulation in females but was unchanged in treated males, which was opposite of renal protein ETA where females were unchanged, and males trended towards reduction. Interestingly, Ednrb and Edn1 trended towards an increase in both the cardiac and renal system in both sexes. However, at the protein level only female cardiac ET-1 was significantly elevated (p<0.0001) while renal ET-1 levels were unchanged. Males demonstrated a significant increase in both cardiac (p=0.0004) and renal ET-1 (p=0.0127). Analysis of female cardiac ETB receptor levels yielded a significant reduction (p=0.0025) and an increasing trend in renal levels. Both cardiac and renal ETB was unchanged in males. The sex differences in the cardiorenal ET system regulation warrants further exploration and possible therapeutic treatments into cardiorenal lupus associated pathologies. Veterans Affairs Biomedical Laboratory Research & Development Career Development Award (CDA-2) 1IK2BX005605-01 to J.P.V.B, Medical University of South Carolina College of Medicine Program Project Grant to and J.P.V.B., and Medical University of South Carolina Core Centers for Clinical Research Project Award P30AR072582 to M.A.C and J.P.V.B. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.