Comparative roles of GRα and MR across physiological systems and disease states.
| Physiological system | GRα—key functions | MR—key functions | Pathogenic imbalance/Clinical consequence |
|---|---|---|---|
| Systemic integration | Master regulator of whole-body homeostasis; coordinates stress adaptation, metabolism, and mitochondrial energy production [58, 83, 84]. | Maintains electrolyte and volume balance; sustains baseline vascular tone [16, 86]. | ↓ GRα → systemic inflammation, mitochondrial failure, and cardiovascular collapse [83]; ↑ MR → hypertension, vascular inflammation, fibrosis [16]. |
| Immune system | Represses excessive inflammation, promotes resolution, restores immune tolerance [83, 85]. | Supports macrophage survival and innate immune activation [85, 87]. | ↓ GRα + ↑ MR → persistent inflammation, cytokine excess, impaired resolution [83, 85]. |
| Cardiovascular/renal | Preserves endothelial integrity via eNOS activation and anti-inflammatory signaling [83, 86]. | Regulates sodium retention, blood pressure, and vascular reactivity [16, 86]. | ↓ GRα → endothelial dysfunction and vascular leakage [83]; ↑ MR → fibrosis, oxidative stress, and cardiometabolic injury [16]. |
| Metabolic/hepatic | Enhances gluconeogenesis under stress; maintains glucose and lipid balance [83, 84]. | Modulates insulin sensitivity and adipose inflammation [16]. | ↓ GRα → energy failure and hypometabolism [83]; ↑ MR → adipose inflammation and insulin resistance [16]. |
| CNS/neuroendocrine | Facilitates stress adaptation, neuroplasticity, and emotional regulation [145, 146]. | Maintains basal excitability, circadian tone, and neuroendocrine stability [146]. | ↑ GRα or ↓ MR → neuroinflammation, oxidative stress, excitotoxicity [145, 146]. |
| Developmental/survival | Required for postnatal viability; integrates transcriptional and non-genomic responses essential for stress tolerance [83, 145]. | Supports perinatal electrolyte and circulatory adaptation [86]. | Deletion of either → postnatal death (GRα = systemic failure; MR = salt-wasting collapse) [83, 86]. |
This table compares the complementary and opposing actions of GRα and MR across major physiological systems. GRα functions as the master integrator of whole-body homeostasis, coordinating metabolic, vascular, immune, and neuroendocrine responses required for stress adaptation and survival. MR primarily maintains electrolyte balance, vascular tone, and tissue-specific homeostasis. Loss of GRα results in multisystem failure, characterized by metabolic and immune collapse, whereas MR loss causes localized salt-wasting and vascular inflammation. Their imbalance underlies many critical-illness phenotypes, where GRα deficiency leads to systemic collapse and MR overactivation promotes inflammation and fibrosis. GRα: glucocorticoid receptor alpha; MR: mineralocorticoid receptor; eNOS: endothelial nitric oxide synthase; CNS: central nervous system. ↑: increased; ↓: decreased; →: leads to/results in.
This work is dedicated to Professor George P. Chrousos’s guidance and mentorship over the past twenty years and to Don Donati, Esq., for his steadfast support of academic freedom and research integrity.
AI-Assisted Work Statement: The content of Table 1 was synthesized from structured evidence obtained via the Consensus research platform and organized with editorial assistance from ChatGPT (OpenAI) to ensure clarity, consistency, and accurate citation. Preparation of the comparative analysis of Tables 2 and 3 was supported by insights derived from Consensus (https://consensus.app), a PubMed-linked AI research synthesis platform used to verify and update biomedical references, and ChatGPT (GPT-5, OpenAI, 2025), which assisted in drafting and formatting the table, integrating reference alignment, and refining academic clarity. Both tools were used exclusively to enhance scientific precision and presentation quality; all final interpretations and conclusions reflect the author’s independent critical analysis. After using the tool/service, author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication.
GUM: Conceptualization, Investigation, Methodology, Writing—original draft, Project administration, Writing—review & editing. The author read and approved the submitted version.
The author has no competing interests to declare or any real or perceived financial interest in any product or commodity mentioned in this paper.
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