| Annotation category | Concise statement | Key supporting citations |
|---|---|---|
| Enzyme identity | Rat **Hsd11b2** (UniProt **P50233**) corresponds to **11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2)**, the oxidative/inactivating member of the 11β-HSD pair; literature consistently distinguishes it from reductive 11β-HSD1. | (pqac-00000003, pqac-00000007) |
| Enzyme reaction | 11β-HSD2 catalyzes **oxidation/inactivation of active glucocorticoids**: **cortisol → cortisone** and **corticosterone → 11-dehydrocorticosterone**. | (pqac-00000007, pqac-00000011) |
| Cofactor | 11β-HSD2 is described as an **NAD+-dependent / NAD-dependent dehydrogenase**, consistent with the SDR-family oxidative direction in epithelia. | (pqac-00000007, pqac-00000008) |
| Substrates/products | Principal substrates are **cortisol** and **corticosterone**; products are the corresponding inactive 11-keto steroids **cortisone** and **11-dehydrocorticosterone**. | (pqac-00000007, pqac-00000011) |
| Primary pathway role | The core biological role is **pre-receptor glucocorticoid metabolism** that protects **mineralocorticoid receptor (MR)** signaling from glucocorticoid excess. By removing cortisol/corticosterone locally, the enzyme enables aldosterone-selective MR activation. | (pqac-00000002, pqac-00000007, pqac-00000010) |
| MR specificity mechanism | In MR target epithelia, glucocorticoids circulate at roughly **100–1000-fold** higher concentrations than aldosterone; 11β-HSD2 prevents these glucocorticoids from occupying MR, thereby conferring aldosterone specificity. | (pqac-00000007, pqac-00000009) |
| Tissue/cell localization | Canonical sites include **distal nephron/kidney**, **colon**, **salivary glands**, and **sweat glands**; these are classic aldosterone-sensitive epithelia. | (pqac-00000002, pqac-00000007, pqac-00000011) |
| Placental/fetal localization | 11β-HSD2 is highly expressed in **placenta/fetal tissues** and functions as a **barrier to maternal glucocorticoids**, limiting fetal cortisol exposure. In placenta, recent human data localize it mainly to **syncytiotrophoblast**. | (pqac-00000002, pqac-00000016, pqac-00000017, pqac-00000032) |
| CNS localization/function | In adult rodents, CNS expression is restricted largely to hindbrain regions including the **nucleus of the solitary tract** and **subcommissural organ**, where 11β-HSD2 supports aldosterone-specific control of **salt appetite** and influences **blood pressure**. | (pqac-00000004, pqac-00000010) |
| Protein family/domain inference | Functional behavior matches the UniProt annotation placing rat Hsd11b2 in the **short-chain dehydrogenase/reductase (SDR)** family, with oxidative steroid dehydrogenase activity. | (pqac-00000003, pqac-00000007) |
| Regulation mechanisms | Recent reviews highlight **epigenetic regulation** of HSD11B2 by **DNA methylation** and **microRNAs** in renal/vascular tissues as an important mechanism in salt-sensitive hypertension. | (pqac-00000021, pqac-00000023) |
| Specific regulatory miRNAs | Reported regulators include **miR-20a** (reduced 11β-HSD2 activity when overexpressed) and **miR-27a-5p** in diet-programmed offspring models; these link environmental inputs to HSD11B2 suppression. | (pqac-00000021, pqac-00000022) |
| Dietary/environmental regulation | Maternal **high-fructose** exposure has been linked to reduced offspring renal Hsd11b2 via miRNA-mediated mechanisms; placental HSD11B2 can also be altered by nicotine, LPS, cadmium/GR signaling, and melatonin-responsive pathways. | (pqac-00000022, pqac-00000016) |
| Phenotypes/models | Loss of 11β-HSD2 function causes **apparent mineralocorticoid excess (AME)** with hypertension, hypokalemia, metabolic alkalosis, and elevated urinary cortisol:cortisone metabolite ratios; brain-selective loss increases salt appetite and can raise blood pressure. | (pqac-00000002, pqac-00000004, pqac-00000026) |
| Rat-relevant functional inference | Although much recent literature is cross-species, rat-relevant annotation is strongly supported because rodent hindbrain, kidney, and placental functions described in reviews align with classic Hsd11b2 biology and with the rat UniProt entry’s enzyme/family assignment. | (pqac-00000003, pqac-00000004, pqac-00000017) |
| Pregnancy/preeclampsia relevance | In 2024 longitudinal steroid profiling, women with preeclampsia showed altered glucocorticoid handling consistent with disturbed **HSD11B2-associated metabolism**; the inferred **11β-HSD2 precursor-to-product ratio was decreased**, and HSD11B2 localized to syncytiotrophoblast. | (pqac-00000013, pqac-00000014, pqac-00000015, pqac-00000032) |
| Clinical/real-world relevance: AME | 2025 case-series data show HSD11B2 deficiency remains clinically actionable: **3 Chinese children** with biallelic variants had low-renin hypertension, hypokalemia, nephrocalcinosis, and growth issues; diagnosis used sequencing and treatment with **spironolactone plus potassium** normalized BP and potassium. | (pqac-00000024, pqac-00000025, pqac-00000028) |
| Clinical/real-world relevance: pseudoaldosteronism | Pharmacologic inhibition of 11β-HSD2 by **licorice/glycyrrhizin/glycyrrhetinic acid** causes pseudoaldosteronism/AME-like physiology; inhibitors are reported as potent, with **low-nanomolar Ki** in review-cited work. | (pqac-00000026, pqac-00000030) |
| Real-world pharmacovigilance data | In a 2024 Japanese adverse-event analysis, **210 pseudoaldosteronism reports** were identified among **2471** complete Kampo AE reports; risk factors included female sex (**OR 1.7**), age ≥70 (**OR 5.0**), low body weight (**OR 2.2**), diuretic use (**OR 2.1**), hypertension (**OR 1.6**), dementia (**OR 7.0**), higher Glycyrrhiza dose (**OR 2.1**), and treatment duration >14 days (**OR 2.8**). | (pqac-00000030) |
| Exposure-associated formulations | In the same 2024 database study, formulas with highest reporting odds for pseudoaldosteronism included **Shakuyaku-kanzoto ROR 18.3 [13.0–25.9]**, **Yokukansan ROR 8.1 [5.4–12.0]**, and **Ryokeijutsukanto ROR 5.5 [1.4–21.9]**. | (pqac-00000030) |
| Quantitative data: steroid binding context | Review data note that ~**90%** of circulating cortisol is CBG-bound and ~**5%** albumin-bound, leaving ~**5% free**; cortisone concentrations are about **10-fold lower** than cortisol but have lower binding affinity, helping explain why local HSD11B2 activity is crucial for receptor selectivity. | (pqac-00000008) |
| Quantitative data: AME rarity | Recent clinical review/case-series context indicates **fewer than 100 AME cases** have been reported worldwide, while **>40 pathogenic HSD11B2 variants** are known, many in exons 3–5. | (pqac-00000025, pqac-00000027) |


*Table: This table summarizes the core functional annotation of rat Hsd11b2/11β-HSD2, including its enzymatic role, localization, regulatory mechanisms, disease relevance, and recent quantitative findings. It integrates key recent review and application-focused sources to support narrative annotation with traceable citations.*