Neuropsychiatric comorbidities, including anxiety, are common in patients with chronic kidney disease (CKD), but the neural circuits and molecular mechanisms that link kidney dysfunction to affective vulnerability remain incompletely defined. The study aimed to identify brain regions and signaling mechanisms that mediate CKD-associated susceptibility to anxiety-like behavior, focusing on the role of peripheral angiotensin II (Ang II) and limbic circuit sensitization.
The investigators established multiple mouse models of CKD and selected an adenine-induced CKD model as the most suitable platform for evaluating neurobehavioral changes. Rather than relying on baseline behavioral readouts alone, the study operationalized anxiety susceptibility as the emergence of anxiety-like behavior after exposure to a subthreshold unpredictable stress (SUS) protocol. Behavioral assays were combined with the SUS paradigm to detect stress-evoked changes that would indicate heightened vulnerability rather than a constitutive anxiety phenotype.
Region-focused c-Fos mapping, fiber photometry recordings of neuronal activity, and chemogenetic approaches were used to interrogate neural circuit activity. Pharmacological and genetic manipulations probed the contribution of Ang II signaling, and in vivo multiphoton microscopy was applied in experiments testing effects of hypothalamic paraventricular nucleus (PVN) activation on renal injury markers.
Across assays, CKD mice did not show a consistent baseline anxiety-like phenotype in standard behavioral tests. However, after exposure to the SUS paradigm, CKD mice developed robust anxiety-like behaviors, indicating enhanced stress susceptibility rather than a persistent baseline anxiety state.
Region-focused c-Fos profiling and fiber photometry pointed to the central amygdala (CeA) as a limbic structure that becomes sensitized in CKD. These approaches identified enhanced CeA recruitment or activity associated with stress exposure in the CKD condition, designating the CeA as a candidate node mediating the behavioral expression of stress-induced anxiety-like behavior.
To test the causal role of CeA activity, the authors used chemogenetic inhibition targeted to CeA GABAergic neurons. Inhibition of these neurons attenuated anxiety-like behavior elicited after SUS in CKD mice, supporting a functional role for CeA circuit activity in the observed behavioral vulnerability. This manipulation links the CeA activity profile to behavioral outcomes in the CKD setting.
Mechanistic experiments examined the renin–angiotensin system as a potential mediator of kidney-to-brain signaling. CKD mice exhibited elevated circulating Ang II, and peripherally administered fluorescently labeled Ang II (FAM-Ang II) produced enhanced accumulation of signal within the CeA, suggesting increased peripheral-to-central Ang II accessibility or CeA sensitivity to systemic Ang II in CKD.
To directly test the contribution of local angiotensin signaling, the study applied a CeA-specific knockdown of Agtr1a, the gene encoding the AT1R. Knockdown of Agtr1a within the CeA attenuated the anxiety-like behavior that emerged after SUS in CKD mice and modified stress-evoked CeA calcium responses. These results indicate that local Ang II–AT1R signaling in the CeA contributes to the behavioral expression of stress-induced anxiety susceptibility in the CKD model.
The authors performed exploratory experiments to evaluate whether brain activation could influence renal pathology. Sustained glutamatergic activation of the hypothalamic paraventricular nucleus (PVN) aggravated early renal injury markers in a mild renal injury model, as assessed using in vivo multiphoton microscopy techniques. These findings provide preliminary evidence for a potential brain-to-kidney feedback loop, wherein limbic or hypothalamic activation may worsen renal injury markers under certain conditions.
The study supports a model in which CKD primes stress-responsive circuits in the central amygdala, increasing behavioral susceptibility to stress-induced anxiety-like responses. Elevated circulating Ang II and enhanced CeA accumulation of peripheral Ang II, together with CeA AT1R dependence of the behavioral phenotype, implicate local Ang II–AT1R signaling as a contributor to CKD-associated affective vulnerability. Exploratory PVN activation data suggest the possibility of reciprocal brain-to-kidney interactions that may aggravate renal injury.
These results identify the CeA Ang II–AT1R axis as a potential mechanistic link between kidney disease and stress-related affective outcomes. The authors declared no competing interests.
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