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Wan-Chen Wu, Kang-Yung Peng, Jin-Ying Lu, Chieh-Kai Chan, Chih-Yuan Wang, Fen-Yu Tseng, Wei-Shiung Yang, Yen-Hung Lin, Po-Chih Lin, Ting-Chu Chen, Kuo-How Huang, Jeff S Chueh, and Vin-Cent Wu

Objective

Concurrent autonomous cortisol secretion (ACS) in patients with primary aldosteronism (PA) is being reported more frequently. Several somatic mutations including PRKACA, GNAS, and CTNNB1 were identified in cortisol-producing adenomas (CPAs). The presence of these mutations in unilateral PA (uPA) patients concurrent with ACS (uPA/ACS) is not well known. This study aimed to investigate the prevalence of these mutations and their clinical vs pathological characteristics in uPA/ACS.

Design

This is a retrospective cohort study.

Methods

Totally 98 uPA patients from the Taiwan Primary Aldosteronism Investigation registry having overnight 1-mg dexamethasone suppression test (DST) and adrenalectomy from 2016 to 2018 were enrolled. Their adrenal tumors were tested for PRKACA, GNAS, and CTNNB1 mutations.

Results

11 patients had CPA-related mutations (7 PRKACA and 4 GNAS). The patients carrying these mutations had higher post-DST cortisol (5.6 vs 2.6 μg/dL, P = 0.003) and larger adenoma (2.2 ± 0.3 vs 1.9 ± 0.7 cm, P = 0.025). Adenomas with these mutations had a higher prevalence of non-classical uPA (72.7% vs 26.3%, P = 0.014). Numerically, slightly more complete clinical success of uPA patients with these mutations was noticed after adrenalectomy, although it was statistically non-significant. Post-DST cortisol levels, adenoma size >1.9 cm, and the interaction of adenoma size >1.9 cm with potassium level were found to be associated with the presence of these mutations.

Conclusion

Our study showed that CPA-related mutations were detected in 36.7% of uPA/ACS adenomas. The presence of these mutations was associated with higher post-DST cortisol levels, larger adenoma sizes, and a high percentage of non-classical uPA. However, these mutations did not significantly affect the clinical and biochemical outcomes after adrenalectomy of uPA/ACS patients but they showed a better trend.

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Zhen-Jie Tong, Chin-Wei Kuo, Po-Cheng Yen, Chih-Ching Lin, Ming-Tsun Tsai, Shing-Hwa Lu, Yi-Ping Chang, Wen-Sheng Liu, Han-Hsing Tsou, Hsiao-Wei Cheng, and Hsiang-Tsui Wang

Objective

Diabetic nephropathy (DN), also known as diabetic kidney disease (DKD), is a major chronic complication of diabetes and is the most frequent cause of kidney failure globally. A better understanding of the pathophysiology of DN would lead to the development of novel therapeutic options. Acrolein, an α,β-unsaturated aldehyde, is a common dietary and environmental pollutant.

Design

The role of acrolein and the potential protective action of acrolein scavengers in DN were investigated using high-fat diet/ streptozotocin-induced DN mice and in vitro DN cellular models.

Methods

Acrolein-protein conjugates (Acr-PCs) in kidney tissues were examined using immunohistochemistry. Renin–angiotensin system (RAS) and downstream signaling pathways were analyzed using quantitative RT-PCR and Western blot analyses. Acr-PCs in DN patients were analyzed using an established Acr-PC ELISA system.

Results

We found an increase in Acr-PCs in kidney cells using in vivo and in vitro DN models. Hyperglycemia activated the RAS and downstream MAPK pathways, increasing inflammatory cytokines and cellular apoptosis in two human kidney cell lines (HK2 and HEK293). A similar effect was induced by acrolein. Furthermore, acrolein scavengers such as N-acetylcysteine, hydralazine, and carnosine could ameliorate diabetes-induced kidney injury. Clinically, we also found increased Acr-PCs in serum samples or kidney tissues of DKD patients compared to normal volunteers, and the Acr-PCs were negatively correlated with kidney function.

Conclusions

These results together suggest that acrolein plays a role in the pathogenesis of DN and could be a diagnostic marker and effective therapeutic target to ameliorate the development of DN.