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

Abstract

Systemic lupus erythematosus (SLE) is a female dominant autoimmune disease that presents with prominent renal injury and hypertension contributing to the morbidity and mortality. While the causality and association of the renal injury and hypertension is not completely understood, novel therapies to reduce these detrimental outcomes could be beneficial to SLE patients. The sigma-1 receptor is a cytoprotective ligand-regulated chaperone protein that acts by decreasing protein aggregation, cellular stress and cell death, thus preventing tissue injury. Activation of the sigma-1 receptor with pharmacological ligands enhances cytoprotection in autoimmune diseases like multiple sclerosis and Huntington’s disease; however, the efficacy of sigma-1 receptor agonists in SLE is not known. We hypothesize that sigma-1 receptor activation with the agonist, LS-1-127, will reduce renal injury and halt the progression of hypertension in SLE mice.Female SLE ( NZBWF1) mice and control ( NZW) mice were weighed and urine collected via metabolic cages weekly starting at 30 weeks of age. Urinary albumin was measured via dipsticks. At 33 weeks of age, SLE and control mice were treated with the sigma-1 receptor ligand (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. Markers of renal injury, including urinary neutrophil gelatinase associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and creatinine were measured by ELISA.Body weight (g) was not different in SLE vs. control mice (39.2 ± 2.9 vs. 35.4 ± 0.9; p=0.44) and LS-1-127 did not alter body weight in SLE mice (39.1 ± 2.2; p=0.97) or controls (34.1 ± 0.6; p=0.84). Albuminuria was present in 44.4% (4 out of 9) of SLE/Veh mice and none of the controls. LS-1-127 did not improve albuminuria in SLE mice (50%; 3 out of 6). MAP (mmHg) was higher in SLE mice compared to control mice (146 ± 4 vs. 123 ± 3; 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). The NGAL-to-creatinine ratio (ng/mg) was higher in the SLE mice compared to controls (327.3±119.8 vs 63.2±4.3, n=9-12, p<0.0007). LS-1-127 treatment did not significantly alter the NGAL-to-creatinine ratio in SLE mice (484.3±209.0, n= 6) or control mice (71.7 ± 5.2, n=10). The KIM1-to-creatinine ratio (ng/mg) was not significantly different between any of the groups.In conclusion, two weeks of sigma-1 receptor activation with LS-1-127 did not significantly alter blood pressure or renal injury in female SLE mice with advanced disease. Further inquiry into the effect of LS-1-127 on the expression of various cellular stress markers in the kidney will be conducted. Also sigma-1 receptor activation at different stages of SLE disease progression warrants investigation. NIH (R01HL153703, K01HL139859) and Department of Defense (LR210096) This is the full abstract presented at the American Physiology Summit 2023 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.