Chronic Stress and the Brain–Kidney Axis in Renal Injury: From Neuroendocrine Dysregulation to Kidney Damage

Abstract

Chronic stress is a pervasive psychophysiological burden and an independent risk factor for chronic kidney disease (CKD). Large-scale cohort studies confirm that stress exposure significantly increases CKD risk and accelerates renal decline, even after adjusting for traditional confounders. However, the neuroendocrine mechanisms translating stress into direct kidney damage remain unclear. This review focuses on the brain–kidney axis, a bidirectional framework integrating neural, endocrine, and immune signals. Under chronic stress, sustained overactivation of the hypothalamic–pituitary–adrenal (HPA) axis and sympathetic nervous system (SNS), coupled with secondary renin–angiotensin–aldosterone system (RAAS) dysregulation, creates a deleterious intrarenal milieu. Unlike classical models driven by high salt or metabolic disorders, a proposed hallmark of stress-induced injury is the non-classical activation of the mineralocorticoid receptor (MR). Given MR’s equal affinity for cortisol and aldosterone, the protective barrier maintained by 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) is compromised under persistent glucocorticoid elevation. This may allow cortisol to escape inactivation and aberrantly activate intrarenal MR, a process putatively termed gluco-mineralo cross-activation. This mechanism is hypothesized to initiate profibrotic cascades via NADPH oxidase 4 (NOX4)/ROS/TGF-β/Smad pathways and amplifies the complement C5a-C5a receptor 1 inflammatory axis, culminating in fibrosis and sclerosis. Based on these insights, we propose stress-related kidney disease (SRKD) as a distinct clinical entity. This review synthesizes current evidence to guide precision interventions targeting the brain–kidney axis.