Abstract P125: Tissue Specific Regulation Of The Cardiac And Renal Endothelin System In A Lupus-prone Mouse Model

Abstract

Systemic Lupus Erythematosus (SLE), the most common form of lupus autoimmune disease, disproportionally affects women (9:1) with high prevalence in African Americans. Numerous studies report elevated endothelin-1 (ET-1) in the plasma of patients with lupus and demonstrate increased ET-1 contribution to various pathological cardiovascular complications including hypertension, cardiac hypertrophy, and heart failure in lupus patients. However, few studies explored the relative roles and regulation of the cardiac and renal ET systems in lupus-associated cardiovascular complications. We hypothesized that immune modulation and acceleration of lupus by a toll-like receptor 7/8 agonist, Resiquimod, would lead to tissue-specific regulation of the ET system in both the kidney and heart in lupus-prone mice. To investigate this, female lupus-prone B6.Nba2 mice were subjected to bi-weekly treatment with the Resiquimod (R848; 100ug/30ul; n=4) or vehicle control (Acetone; n=5) for one month and subsequently studied for 12 weeks. At 16 weeks post-treatment (30 weeks old), heart and kidneys were collected, and the ET system was analyzed by RT-PCR, immunoblotting, and immunohistochemistry. R848 treatment significantly increased cardiac but not kidney expression of ET-1 (19.90 ± 1.36 vs. 7.65 ± 0.54 pg/mg; p=0.02 compared to controls (6.10 ± 1.64 vs. 4.95 ± 0.55 pg/mg; p>0.05). Furthermore, R848 treated mice had no significant effect on cardiac endothelin receptor A (ET A ) nor endothelin receptor B (ET B ) expression at both the RNA and protein levels (p>0.05 for all). Interestingly, renal ET B RNA expression was reduced (0.08 vs. 1.62; p <0.05), while ET A expression was unchanged (p > 0.05) with R848. The same trend was observed at the protein level by immunoblotting and immunohistochemistry (p>0.05) Our results provide evidence that lupus acceleration with TLR7/8 activation in B6.Nba2 mice differentially regulates tissue-specific ET systems in the heart and kidney, potentially contributing to the tissue specific dysfunction found in lupus. These findings suggest that our model offers an opportunity to identify cardiac and renal contributions to lupus complications, and specifically determine the cell-specific regulation of ET biosynthesis and signaling.