Abstract MP24: Selective Activation Of DMV Neurons Improves Renal Injury In Systemic Lupus Erythematosus

Abstract

The cholinergic anti-inflammatory pathway is a vagally-mediated mechanism that controls inflammation. Our published data suggest that an impaired cholinergic anti-inflammatory pathway contributes to hypertension and renal disease in female mice with systemic lupus erythematosus (SLE), since pharmacological potentiation of the efferent vagus via administration of galantamine reduces renal inflammation, mean arterial pressure (MAP) and glomerulosclerosis. The aim of the current study is to selectively target neurons within the dorsal motor nucleus of the vagus (DMV) to stimulate the efferent vagus and the cholinergic anti-inflammatory pathway using designer receptors exclusively activated by designer drugs (DREADDs). We hypothesized that selective activation of DMV neurons would reduce inflammation, eliminating the associated end organ damage in SLE. To study this, female SLE ( NZBWF1 ) and parental control ( NZW ) mice received bilateral microinjections of pAAV-hSyn-hM3D(Gq)-mCherry or pAAV-hSyn-mCherry (control virus) into the DMV at 31 weeks of age using the following coordinates with calamus as reference: 0 mm caudal, 0.25 mm lateral and 0.48 mm ventral. Two weeks post-microinjection, DREADD agonist CNO (3mg/kg) was administered subcutaneously for 2 weeks starting at 33 weeks. At 35 weeks, mice were housed in metabolic cages for urine collection and catheters were implanted in the carotid artery for MAP measurement. Mice were subsequently euthanized and the brain collected to confirm the site of virus microinjection. Selective activation of DMV neurons decreased the incidence of albuminuria [> 300 mg/dL; 66% (4 out of 6) vs. 0% (0 out of 7)], urinary leukocytes [62.5% (5 out of 8) vs. 50% (3 out of 6)] and blood in the urine [50% (4 out of 8) vs. 16% (1 out of 6)] in SLE mice. MAP did not significantly change with the chemogenetic activation of DMV neurons in SLE mice or parental controls (SLE/control virus: 146 ± 6, n=7; SLE/Gq DREADD: 142 ± 3, n=6; NZW/control virus: 126 ± 4, n=4; NZW/Gq DREADD: 132 ± 2, n=5). These results suggests that this timeline of selective activation of DMV neurons in SLE mice reduces renal injury without altering blood pressure, but future studies will confirm the effect on hypertension and renal inflammation in SLE mice