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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>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\u2013kidney axis, a bidirectional framework integrating neural, endocrine, and immune signals. Under chronic stress, sustained overactivation of the hypothalamic\u2013pituitary\u2013adrenal (HPA) axis and sympathetic nervous system (SNS), coupled with secondary renin\u2013angiotensin\u2013aldosterone 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\u2019s equal affinity for cortisol and aldosterone, the protective barrier maintained by 11\u03b2-hydroxysteroid dehydrogenase type 2 (11\u03b2-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-\u03b2\/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\u2013kidney axis.<\/jats:p>","DOI":"10.3390\/ijms27188356","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T14:23:56Z","timestamp":1790864636000},"page":"8356","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chronic Stress and the Brain\u2013Kidney Axis in Renal Injury: From Neuroendocrine Dysregulation to Kidney Damage"],"prefix":"10.3390","volume":"27","author":[{"given":"Chunyun","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiwen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3565-8024","authenticated-orcid":false,"given":"Chun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1016\/j.ekir.2020.12.032","article-title":"Stress Related Disorders and the Risk of Kidney Disease","volume":"6","author":"Su","year":"2021","journal-title":"Kidney Int. 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