Central delivery of an acetylcholinesterase inhibitor reverses cardio-renal pathology in lupus mice

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by unresolved systemic inflammation that may drive cardio-renal pathology, including hypertension secondary to kidney inflammation. Because SLE is associated with central autonomic dysfunction and reduced activation of the cholinergic anti-inflammatory pathway (CAP), we hypothesized that restoring central cholinergic signaling would ameliorate peripheral inflammatory and cardio-renal pathologies. Galantamine (GAL), an acetylcholinesterase inhibitor that increases acetylcholine bioavailability and robustly engages CAP-mediated anti-inflammatory signaling, has recently been repurposed as an immunomodulatory agent in preclinical and clinical studies. To directly test whether central cholinergic activation is sufficient to modulate systemic disease processes in SLE, we infused GAL or saline (SAL) intracerebroventricularly (ICV) and continuously for two weeks via osmotic minipumps and assessed its impact on hypertension and renal inflammation in 33 week female NZBWF1 (SLE) and NZW control (CTRL) mice. At 35 weeks, mean arterial pressure (MAP) was measured via carotid catheter and renal inflammation was assessed by Western blot. MAP was elevated in SLE-SAL mice compared to CTRL-SAL (158.0 ± 5.5 vs. 132.5 ± 5.4 mmHg, P=0.0234), and ICV-GAL significantly reduced MAP in SLE mice to control levels (132.2 ± 2.4 mmHg, P=0.0212). Renal cortical expression of the 26 kDa transmembrane form of TNF-α was significantly increased in SLE-SAL mice compared to CTRL-SAL mice (1.37e8 ± 1.34e7 vs. 1.77e7 ± 1.55e7, P< 0.0001). ICV-GAL significantly reduced TNF-α expression in SLE mice (7.23e7 vs 4.71e6, P=0.0037). Similarly, the biologically active 52 kDa homotrimer form of TNF-α was significantly increased in SLE-SAL mice compared to CTRL-SAL mice (1.20e8 ± 1.35e7 vs. 6.55e6 ± 2.19e6, P< 0.0001). ICV-GAL treatment significantly reduced TNF-α expression in SLE (4.85e7 ± 1.03e7, P< 0.0001). Our data suggests that central delivery of GAL is sufficient to normalize blood pressure and suppress renal inflammation in SLE, indicating a dominant central mechanism driving cardio-renal pathology. The rescue phenotype suggests that restoring central acetylcholine bioavailability reactivates vagally-mediated autonomic anti-inflammatory pathways like the CAP. Importantly, our prior chemogenetic activation of vagal effferents from the dorsal motor nucleus did not improve MAP or renal inflammation, suggesting that GAL recruits additional brainstem cholinergic nuclei, such as nucleus tractus solitarius and nucleus ambiguus, that are required for full autonomic-immune modulation. Together, these results identify the central nervous system as a critical and previously underappreciated therapeutic target in SLE-associated hypertension and renal injury. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.