Jinbo Hu

BACKGROUND: The adrenal zona glomerulosa (zG) is the primary site of aldosterone synthesis. Inducible genetic tools are important for investigating zG cell function and fate in adult mice. This study aimed to generate and validate a tamoxifen-inducible, zG-specific aldosterone synthase–CreERT2 mouse model and investigate the zG-specific role of NPC1 (Niemann-Pick type C1) in aldosterone synthesis. METHODS: Aldosterone synthase-CreERT2 mice were generated by clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat–associated 9 knock-in of P2A (porcine teschovirus-1 2A peptide)-CreERT2 into the Cyp11b2 locus. Cre specificity and efficiency were validated by quantitative polymerase chain reaction, immunofluorescence, and lineage tracing. The model was then used to conditionally delete Npc1 in the zG. RESULTS: Cre expression and activity were confined to the zG. Heterozygous aldosterone synthase–CreERT2 mice showed normal adrenal morphology and hormone levels despite reduced Cyp11b2 expression. Homozygosity of the CreERT2 allele significantly reduced Cyp11b2 expression and aldosterone levels and increased renin in both sexes, indicating a gene-dosage effect. Lineage tracing confirmed the centripetal migration of zG cells to the zona fasciculata, which was faster in female mice. Strikingly, zG-specific Npc1 deletion reduced aldosterone in female mice under a normal-sodium diet, whereas increased renin and decreased aldosterone-to-renin ratio were observed in male mice under a high-sodium diet, indicating a sex-dependent effect. CONCLUSIONS: The aldosterone synthase–CreERT2 mouse provides a powerful and specific platform for spatiotemporally controlled dissection of zG biology, with the heterozygous line recommended for use to avoid Cre-associated dosage effects. Using this model, we identify a sex-dependent effect of zG-specific Npc1 deletion on aldosterone regulation, providing new insight into sex differences in adrenal physiology and aldosterone-related disorders.

Introduction: The 2025 Endocrine Society Guideline expands PA screening to all patients with hypertension, even on interfering medication, and recommends repeat testing when appropriate, while adopting a more stratified approach to subsequent diagnostic evaluation. Materials and Methods: In this simulation, we evaluated two guideline-directed screening and management strategies for PA in a cohort of patients with newly diagnosed hypertension. By developing a decision tree-Markov model and incorporating relevant parameters from epidemiological surveys and literature, we analyzed the cost-effectiveness with Quality-Adjusted Life Years (QALYs) and the incremental cost-effectiveness ratio (ICER). The model's reliability was evaluated through the sensitivity analysis. Results: Within the Chinese healthcare setting, the updated guideline dominated the original strategy (cost: 3329.77USD vs. 3568.29USD; QALYs: 10.85 vs. 10.82), yielding an ICER of −7950.67USD/QALY. Across multiple scenario analyses, including alternative healthcare-cost settings and higher MRA treatment costs, the updated Guideline remained economically favorable. Sensitivity analyses and model validation further supported the overall stability and plausibility of the findings. Conclusions: Over a 30-year horizon, management of PA under the updated Guideline is more cost-effective than the original Guideline.

BACKGROUND: Somatic aldosterone-driver mutations are identified in >90% of patients with primary aldosteronism undergoing adrenalectomy, and they display distinct demographic clustering. ATP1A1 and ATP2B3 mutations, encoding the Na ⁺ /K ⁺ ATPase α1 subunit and the Ca ²⁺ ATPase 3, respectively, are relatively rare and are often grouped as ATPase mutations. Differences in their clinical and biochemical phenotypes remain understudied. METHODS: This international collaboration of 16 centers included patients with primary aldosteronism harboring pathogenic variants in ATP1A1 and ATP2B3 . Clinical data were collected from medical records. Where available, we compared histopathologic features and steroid profiles (from peripheral and adrenal vein samples) by liquid chromatography-tandem mass spectrometry. RESULTS: We included 300 patients (mean age, 57±11 years; 85% men) with aldosterone-producing lesions harboring ATP1A1 (204) and ATP2B3 (96) mutations. Age and sex distributions were similar. ATP2B3 mutations were associated with lower serum potassium, higher lateralization indices, and stronger contralateral suppression. Postoperative biochemical cure was achieved in 96% of patients with ATP2B3 mutations versus 83% of those with ATP1A1 mutations ( P =0.02). Multiple CYP11B2-positive lesions were observed in 47% of ATP1A1 versus 27% of ATP2B3 cases ( P =0.03). Baseline peripheral steroid profiling was available in 126 patients (84 with ATP1A1 and 42 with ATP2B3 ) and showed higher aldosterone concentrations in the ATP2B3 group (median [interquartile range], 31 ng/dL [20–43] versus 23 ng/dL [11–38]; P =0.03). CONCLUSIONS: ATP ase mutations are most common in middle-aged men with lateralized primary aldosteronism. Compared with ATP1A1 , ATP2B3 mutations are associated with a more severe primary aldosteronism phenotype, stronger lateralization, and higher rates of single aldosterone-producing lesions and postoperative biochemical cure.

Background: Guidelines suggest that the risk of mortality in diabetic foot disease (DFD) is comparable to that of cancer; however, high‐quality evidence is lacking. We aimed to compare the mortality of DFD with that of various cancers based on data from international cohorts. Methods: We defined DFD according to the IWGDF 2023 guidelines, and cancer was defined based on the ICD‐10 codes. We included 527, 1784, and 601 patients with DFD and 1219, 100,643, and 152 patients with cancer from the National Health and Nutrition Examination Survey (NHANES), UK Biobank (UKB), and Chongqing Diabetes Registration (CDR) cohorts, respectively. We compared the risk of mortality between DFD and overall or site‐specific cancers in the same cohort. Results: Patients with DFD showed 38%, 45%, and 499% higher risks of mortality than patients with overall cancer in the NHANES, UKB, and CDR. For site‐specific cancer, the risk of mortality was significantly higher in DFD than in skin cancer (hazard ratio 10.69, 95% CI: 1.37–2.07 in NHANSE; 3.8, 3.72–448 in UKB), breast cancer (1.35, 1.0–1.83 in NHANSE; 1.95, 1.67–227 in UKB), and prostate cancer (1.4, 1.8–179 in NHANSE; 2.61, 2.35–289 in UKB). The mortality rate of DFD is similar to that of most types of cancer, such as colon cancer, lymphoma, and kidney cancer, and is lower than that of a minority of cancers, including lung, pancreatic, and liver cancers. Conclusion: Patients with DFD have a higher risk of mortality than overall cancer, particularly skin, breast, and prostate cancers.

BACKGROUND: Primary aldosteronism (PA) is a common and treatable cause of hypertension, yet data on the durability of medical treatment response beyond the first year are limited. Using the PA medical treatment outcomes framework, we evaluated long-term biochemical and clinical outcomes and factors associated with treatment response. METHODS: We conducted an international, multicenter, observational cohort study across 27 centers on 4 continents. Adults with PA treated with mineralocorticoid receptor antagonists and/or epithelial sodium channel blockers between 2016 and 2021 were included if follow-up data were available at ≥12 months. Biochemical and clinical responses were classified as complete, partial, or absent using PA medical treatment outcomes criteria. Ordinal logistic regression identified determinants of a favorable treatment response. RESULTS: The cohort included 1292 patients (47.5% women, mean age 52 years) with a median follow-up of 34 months (interquartile range, 21–51). At ≥12 months, 58.3% achieved a complete biochemical response, and 20.8% achieved a complete clinical response, with only 5% showing no response. Determinants of a favorable biochemical response included lower aldosterone and lateralization index, and higher renin and potassium levels at baseline. In those taking spironolactone, a higher daily dose was also associated with a favorable biochemical response. Determinants of a favorable clinical response included female sex, lower body mass index, shorter duration of hypertension, and absence of hypertension-mediated organ damage. CONCLUSIONS: Targeted medical therapy for PA can deliver sustained biochemical and clinical benefits. Early disease detection and adequate dose titration are highly actionable determinants of long-term treatment success.

C-X-C motif chemokine receptor 4 (CXCR4) is highly expressed in aldosterone-producing adenoma, and gallium-68 pentixafor PET-CT imaging targeting CXCR4 has been utilized for subtype diagnosis in primary aldosteronism. However, the roles of CXCR4 in regulating aldosterone biosynthesis remain poorly understood. In this study, we observed a strong co-localization of aldosterone synthase (CYP11B2) and CXCR4 in aldosterone-producing adenoma and other aldosterone-producing lesions. Functional experiments in H295R cells revealed that CXCR4 overexpression significantly suppressed both aldosterone synthesis and CYP11B2 expression, whereas CXCR4 knockdown conversely enhanced aldosterone production and up-regulated CYP11B2. Mechanistically, CXCR4 inhibited aldosterone biosynthesis by up-regulating inhibitor of DNA binding (ID) proteins, which directly repressed CYP11B2 transcription. Our data demonstrate that in aldosterone-producing lesions, CXCR4 expression is consistently elevated alongside CYP11B2, indicating a potential compensatory mechanism to counteract elevated aldosterone levels.

BACKGROUND: Aldosterone-producing adenoma is a major cause of primary aldosteronism. However, the molecular mechanisms underlying aldosterone overproduction remain incompletely understood. The expression of peptide deformylase, which is essential for the maturation of mitochondrially encoded proteins, was significantly upregulated in our previous proteomic analysis. We aimed to elucidate the role of peptide deformylase in aldosterone overproduction. METHODS: Peptide deformylase expression was validated in enlarged aldosterone-producing adenoma samples harboring different mutations and in adrenocortical cell lines. A key protein exhibiting the most significant change was identified through proteomic analysis of peptide deformylase-knockdown cells and validated in vitro. RESULTS: Both peptide deformylase expression and aldosterone synthase (CYP11B2 [cytochrome P450 family 11 subfamily B member 2]) colocalization were significantly enhanced in aldosterone-producing adenoma samples. Among the 43 genotyped cases, peptide deformylase upregulation was most pronounced in KCNJ5 - and ATP1A1 -mutant tumors, and its expression was positively correlated with CYP11B2 expression, plasma aldosterone levels, and the aldosterone-to-renin ratio. In H295R cell (human adrenocortical carcinoma cell line, NCI-H295R cell), peptide deformylase overexpression increased aldosterone production, whereas peptide knockdown inhibited aldosterone production. Furthermore, proteomic analysis revealed that peptide deformylase deficiency significantly upregulated the expression of CALB1 (calbindin 1), which is a key cytosolic calcium-buffering protein. Additional data highlighted the CALB1-calcium axis as a key regulator of CYP11B2 expression and aldosterone production and showed that peptide deformylase may modulate CALB1 expression through TBX2 (T-box transcription factor 2)–dependent transcriptional regulation. CONCLUSIONS: Peptide deformylase regulates CYP11B2 expression and aldosterone production. The CALB1-calcium signaling pathway may mediate the effects of peptide deformylase on aldosterone overproduction.

This study aimed to explore the association between leukocyte telomere length (LTL) and premature rupture of membranes (PROM). This cross-sectional study included a total of 170,841 participants from the UK Biobank. Restricted cubic spline model (RCS) and logistic regression were used to evaluate the relationship between LTL and PROM. Subgroup analysis and interaction tests were conducted to test the stability of the results. RCS model showed a notable non-linear association between LTL and PROM. The logistic regression model further revealed that longer LTL was associated with an increased odds of developing PROM after fully adjusting for confounding factors. For every 1 unit increase in the original LTL, the odds of PROM significantly increases by 1.97 times (OR = 1.97, 95% CI:1.30–2.95). Compared with the Q1 of LTL, the PROM odds of Q3 and Q4 increased by 33% (OR = 1.33, 95% CI: 1.11–1.59) and 31% (OR = 1.31, 95% CI: 1.09–1.56). Finally, subgroup analysis found that age and education level play an important role in regulating the relationship between LTL and the odds of PROM. The research results indicate a non-linear relationship between LTL and PROM, and longer LTL is associated with higher PROM odds, which is influenced by age and education level.