Central MANF Attenuates Endoplasmic Reticulum Stress-induced Hemodynamic Responses and Sympathetic Outflow

Lei Tong; Yang Yu; Shunguang Wei

doi:10.1152/physiol.2026.41.S1.2300564

Abstract only Endoplasmic reticulum (ER) stress in the brain has been implicated in the pathophysiology of hypertension and heart failure. We previously demonstrated that central inhibition of ER stress with tauroursodeoxycholic acid in heart failure rats reduces renin–angiotensin system activation and sympathetic overactivity. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a stress-responsive protein essential for maintaining cellular homeostasis and viability, particularly under ER stress, through its ability to modulate the unfolded protein response. Our prior work showed that MANF is selectively expressed in neurons, especially within neurohumoral and autonomic regulatory centers; however, its role in the brain in modulating cardiovascular function and sympathetic outflow remains unclear. In this study, we examined the impact of MANF on hemodynamic control and sympathetic drive using electrophysiological recordings in urethane-anesthetized male Sprague–Dawley rats. The ER stress inducer tunicamycin (3 μg), an AAV-mediated MANF siRNA, or recombinant human MANF (rhMANF) was administered via intracerebroventricular (ICV) injection. Mean arterial pressure (MAP, mmHg), heart rate (HR, bpm), and renal sympathetic nerve activity (RSNA, % change from baseline) were continuously monitored for 4–5 hours. Compared with vehicle controls, tunicamycin significantly (*p < 0.01) increased MAP (11.4 ± 3.9*), HR (73.2 ± 4.3*), and RSNA (68.3 ± 10.1*). Similarly, MANF knockdown elevated MAP (9.2 ± 4.7*), HR (54.3 ± 3.7*), and RSNA (28.6 ± 7.8*). In contrast, restoring central MANF levels with ICV rhMANF markedly blunted the excitatory responses induced by MANF deficiency, reducing MAP from 96.7 ± 4.3 to 82.2 ± 4.6*, HR from 382.6 ± 4.2 to 351.3 ± 3.3*, and RSNA from 21.3 ± 3.5 to 8.9 ± 1.4*. These results indicate that ER stress and neuronal MANF critically influence central regulation of hemodynamics and sympathetic outflow, and suggest that MANF functions as an endogenous protective factor that counteracts ER stress–driven cardiovascular dysregulation and sympathetic overactivity. Targeting MANF may represent a promising therapeutic strategy for conditions characterized by ER stress–associated neurohumoral activation and autonomic imbalance, including hypertension and heart failure. This study was supported by NIH R01 NIH R01 HL155091 to SG Wei. 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.

Central MANF Attenuates Endoplasmic Reticulum Stress-induced Hemodynamic Responses and Sympathetic Outflow

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