Effect of Sigma-1 Receptor Activation on Renal Injury and Hypertension in Female Mice with Lupus

Date

2023

Authors

Dinh, Viet
Chaudhari, Sarika
Shimoura, Caroline
Tucker, Selina
Essajee, Salman
Warne, Cooper

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0000-0001-6472-8648 (Dinh, Viet)

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Abstract

Systemic lupus erythematosus (SLE) is a female-dominant autoimmune disease with prominent renal injury and hypertension, contributing to its morbidity and mortality. Novel therapies to reduce these detrimental outcomes could be beneficial to SLE patients. The sigma-1 receptor (S1R) is a cytoprotective ligand-regulated chaperone protein that decreases protein aggregation, cellular stress, and cell death, thus preventing tissue injury. S1R activation with pharmacological ligands enhances cytoprotection in autoimmune diseases like multiple sclerosis and Huntington’s disease; however, the efficacy of S1R agonists in SLE is unknown. We hypothesize that S1R activation via the agonist LS-1-127 will reduce renal injury and halt the progression of hypertension in SLE mice.

Female SLE (NZBWF1) and control (NZW) mice were weighed and urine collected via metabolic cages weekly starting at 30 weeks of age. Albuminuria was measured via dipsticks. At 33 weeks of age, SLE and control mice were treated with LS-1-127 (10 mg/kg IP) or equal volume of vehicle (10% DMSO; IP) three times a week for two weeks. At 35 weeks, mean arterial pressure (MAP) was measured in conscious mice using indwelling carotid catheters for two consecutive days and then mice were euthanized. Wire myography was used to assess potassium chloride (KCl)-induced contraction and acetylcholine (ACh)-induced relaxation in excised aorta. Markers of renal injury – urinary neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and creatinine – as well as plasma double-stranded (ds)DNA autoantibodies were measured by ELISA.

Albuminuria was present in 44.4% (4 of 9) of SLE mice and no controls. LS-1-127 did not improve albuminuria in SLE mice (50%; 3 of 6). NGAL:creatinine ratio (ng/mg) was higher in SLE mice compared to controls (327.3 ± 119.8 vs 63.2 ± 4.3 ng/mg; n=9–12; P=0.0007). LS-1-127 did not significantly alter NGAL:creatinine ratio in SLE mice (484.3 ± 209.0; n=6) or controls (71.7 ± 5.2; n=10). KIM1:creatinine ratio (ng/mg) did not differ between groups. dsDNA autoantibodies were higher in SLE mice compared to controls (6.9e5 ± 1.1e5 vs. 1.4e5 ± 3.1e4 U/mL; n=9–10; P<0.0001). LS-1-127 did not significantly alter dsDNA autoantibodies in SLE mice (7.1e5 ± 1.2e5; n=6) or controls (1.5e5 ± 4.0e4; n=10). MAP was higher in SLE mice compared to controls (146 ± 4 vs. 123 ± 3 mmHg; n=9–10; P <0.0001). LS-1-127 did not significantly alter MAP in SLE mice (150 ± 8; n=6) or controls (124 ± 2; n=10). KCl-induced aortic contraction was similar in SLE and controls (21 ± 7 vs. 25 ± 4 mM, n=3–4). Sensitivity to KCl after LS-1-127 treatment was 11 ± 3 and 21 ± 2 mM in SLE and controls (n=2–4). ACh-induced aortic relaxation did not differ between groups.

In conclusion, two weeks of S1R activation with LS-1-127 did not significantly alter markers of renal injury, autoimmunity, blood pressure, or vascular reactivity in female SLE mice with advanced disease. Further inquiry into the effect of LS-1-127 on the expression of renal proinflammatory cytokines will be conducted. S1R activation at different stages of SLE disease progression also warrants future investigation.

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Research Appreciation Day Award Winner - School of Biomedical Sciences, 2023 Department of Physiology & Anatomy-Integrative Physiology Program - 2nd Place

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