In our single-center cross-sectional study, we investigated the prevalence of PA in patients with T2DM and hypertension. Additionally, we observed clinical manifestations in both the PA group and the EH group. Our findings provide valuable insights into the coexistence of these conditions.
Our study revealed that the prevalence of PA among T2DM patients with hypertension was 22.1%. This finding aligns with our previous finding of a prevalence of at least 19% in newly diagnosed T2DM patients with hypertension[4]. A Japanese study also reported a 21.6%[5] prevalence of diabetes in patients with PA. These findings collectively emphasize the common occurrence of these two diseases and underscore the need for vigilance when dealing with their coexistence.
Notably, our research indicated that male PA patients were more likely to develop obesity, and the PAC was positively correlated with BMI in this subgroup. The World Health Organization (WHO) defines overweight as a BMI ≥ 25 kg/m2 and obesity as a BMI ≥ 30 kg/m2. However, Asian individuals, even those with a BMI ≤ 25 kg/m2, have an increased risk of diabetes and cardiovascular diseases. Therefore, in China, overweight is defined as a BMI ≥ 24 kg/m2, while obesity is defined as a BMI ≥ 28 kg/m2[3]. Our study used these criteria to define obesity. The relationship between sex and the RAAS has been inconsistent across various studies. Visceral obesity and insulin resistance have been associated with an elevated PAC in normotensive women[6], while male PA patients are more prone to obesity and obesity-related metabolic disorders[7–10]. This intricate connection between aldosterone and visceral obesity involves adipose tissue-secreted factors stimulating aldosterone production. Moreover, mineralocorticoid receptor (MR) expression increases during white adipocyte differentiation, contributing to adipose tissue inflammation, oxidative stress, fibrosis, and insulin resistance[11]. Therefore, obese male T2DM patients with hypertension should be closely monitored for the possibility of PA.
Our study revealed that female T2DM patients with PA had a greater incidence of proteinuria, which was positively correlated with the PAC. Previous research has indicated a positive correlation between the PAC and left ventricular wall thickness in premenopausal women[12]. Additionally, aldosterone blockers such as eplerenone have been demonstrated to be effective at reducing cardiac remodeling in female mice[13]. Diabetes mellitus (DM) independently predicts renal function decline in female PA patients treated with spironolactone[14], underscoring the clinical significance of addressing this comorbidity. PA combined with DM has been associated with poorer clinical outcomes and increased all-cause mortality[15]. Importantly, the RAAS plays a role in the development of diabetic renal complications[16, 17], with MR expression and transcriptional activity increasing under high-glucose conditions[18]. In conclusion, early detection and treatment of PA in female patients hold promise for improving long-term renal outcomes.
Our study also revealed significant sex differences in the serum levels of BNP, ANP, leptin, adiponectin, CXCR4 and CXCL12. These serum biochemical markers were found to be correlated with BMI. Importantly, in female patients, the PAC was positively correlated with the serum concentrations of CXCR4 and CXCL12. These findings suggest that distinct pathophysiological mechanisms may be involved in patients with PA of different sexes. BNP and ANP, which are members of the natriuretic peptide (NP) family, serve as common markers of cardiac volume. NPs have diuretic, natriuretic, and vascular relaxation effects and play pivotal roles in cardiovascular, endocrine, renal, and vascular homeostasis[19–21]. The NP family is the target of the novel antihypertensive agent sacubitril/valsartan. Notably, circulating NP levels tend to be lower in patients with obesity and diabetes [22] but are elevated in those with PA. Our study indicated no significant difference between BNP and ANP in patients with PA combined with T2DM. Leptin, which is produced primarily by adipose tissue, is present at higher serum levels in obese individuals than in nonobese individuals[23]. Elevated circulating leptin levels are associated with increased renal sympathetic tone in overweight individuals and are involved in insulin secretion and peripheral tissue sensitivity[24–26]. Leptin is also associated with hypertension, atherosclerosis[27], and decreased kidney function[28]. Importantly, our results showed that a higher BMI in females corresponded to significantly elevated leptin levels, suggesting a potential avenue for the treatment of hypertension-related complications in women through modulation of the leptin-aldosterone axis. CXCL12, an agonist of the G protein-coupled receptor CXCR4, is widely expressed and influences angiogenesis and leukocytes, playing roles in various pathologies, including cancer and autoimmune and inflammatory disorders[29]. The expression patterns of CXCR4 and aldosterone synthetase in the adrenal cortex have led to the use of 68Ga-Pentixafor-PET/CT for subtype diagnosis of PA[30]. However, to the best of our knowledge, there is limited research on the expression of CXCL12 and CXCR4 in the serum of PA patients. Our study revealed a positive correlation between serum CXCR4/CXCL12 concentrations and the PAC in female patients, indicating the potential role of CXCL12/CXCR4 in both local adrenal aldosterone synthetase expression and systemic regulation. Previous research has shown that increased serum CXCL12 levels are associated with major adverse cardiovascular events[31, 32]. Additionally, the CXCL12/CXCR4 axis has implications for diabetic nephropathy, with increased CXCR4 expression observed in renal biopsy tissues of diabetic nephropathy patients[33]. Our findings suggest that the high expression of CXCR4/CXCL12 in women may be associated with sex-specific kidney damage in PA patients. Activation of the NOD-like receptor protein 3 inflammasome (NLRP3) pathway by CXCR4 has been shown to induce neuronal inflammation[34], while the MR antagonist eplerenone inhibits chronic inflammation development by blocking NLRP3 inflammasome activation signals in adipose tissue and the liver of high-fat diet mice[11]. Currently, there is limited research on the correlation between PA and immune regulation, suggesting that further investigation into the involvement of CXCR4/CXCL12 in kidney damage related to PA combined with T2DM is worthwhile. Future studies may explore sex-specific antihypertensive drug efficacy, revealing the clinical significance of this drug for the treatment of PA.