We identified a p53 target gene, phosphate-activated mitochondrial glutaminase (GLS2), a key enzyme in conversion of glutamine to glutamate, and thereby a regulator of glutathione (GSH) synthesis and energy production. GLS2 expression is induced in response to DNA damage or oxidative stress in a p53-dependent manner, and p53 associates with the GLS2 promoter. Elevated GLS2 facilitates glutamine metabolism and lowers intracellular reactive oxygen species (ROS) levels, resulting in an overall decrease in DNA oxidation as determined by measurement of 8-OH-dG content in both normal and stressed cells. Further, siRNA down-regulation of either GLS2 or p53 compromises the GSH-dependent antioxidant system and increases intracellular ROS levels. High ROS levels following GLS2 knockdown also coincide with stimulation of p53-induced cell death. We propose that GLS2 control of intracellular ROS levels and the apoptotic response facilitates the ability of p53 to protect cells from accumulation of genomic damage and allows cells to survive after mild and repairable genotoxic stress. Indeed, overexpression of GLS2 reduces the growth of tumor cells and colony formation. Further, compared with normal tissue, GLS2 expression is reduced in liver tumors. Thus, our results provide evidence for a unique metabolic role for p53, linking glutamine metabolism, energy, and ROS homeostasis, which may contribute to p53 tumor suppressor function.glutathione antioxidant | glutaminolysis | tumor suppression | apoptosis

Abbreviations & Acronyms APA = aldosterone-producing adenoma BMI = body mass index BP = blood pressure CKD = chronic kidney disease eGFR = estimated glomerular filtration rate EH = essential hypertension FBGL = fasting blood glucose level GFR = glomerular filtration rate IHA = idiopathic hyperaldosteronism mo = months PA = primary aldosteronism PAC = plasma aldosterone concentration PRA = plasma renin activity Postop. = postoperative Preop. = preoperative SD = standard deviation TC = total cholesterol TG = triglycerides Objective: Correct interpretation of renal function in patients with primary aldosteronism is difficult before adrenalectomy, because subtle kidney impairment is often masked by glomerular hyperfiltration peculiar to primary aldosteronism. The aim of this study was to investigate postoperative changes in renal function for patients with primary aldosteronism and to identify clinical predictors of chronic kidney disease manifested postoperatively in the patients without pre-existing chronic kidney disease. Methods: Records of 78 Japanese patients who underwent unilateral adrenalectomy for primary aldosteronism were retrospectively surveyed. Patients who had been followed up for <6 months were excluded. Preoperative and postoperative estimated glomerular filtration rate were compared. Furthermore, uni-and multivariate analyses were carried out to identify clinical predictors for chronic kidney disease manifested postoperatively. Results: Patients with preoperative estimated glomerular filtration rate Ն60 mL/min/ 1.73 m 2 showed a significant decrease after surgery. Of the 66 patients without preexisting chronic kidney disease, 24 developed chronic kidney disease postoperatively. Multivariate logistic regression analysis identified a medical history of dyslipidemia as an independent predictor for chronic kidney disease manifested postoperatively. According to univariate analyses, additional factors associated with postoperative manifestation of chronic kidney disease included older age, lower diastolic blood pressure and lower estimated glomerular filtration rate. Conclusions: The interpretation of normal or abnormal renal functions by examining estimated glomerular filtration rate heightened by hyperfiltration alone can mislead clinicians before adrenalectomy. Clinicians should pay attention to patients at greater risk of a significant decline in postoperative renal function.

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Objective Accurate assessment and localization of aldosterone-producing adenomas (APAs) are essential for the treatment of primary aldosteronism (PA). Although adrenal venous sampling (AVS) is the standard method of reference for subtype diagnosis in PA, controversy exists concerning the criteria for its interpretation. This study aims to determine better indicators that can reliably predict subtypes of PA. Method Retrospective, single-cohort analysis including 209 patients with PA who were subjected to AVS. Eighty-two patients whose plasma aldosterone concentrations (PAC) were normalized after surgery were histopathologically or genetically diagnosed with APA. The accuracy of image findings was compared to AVS results. Receiver operating characteristic (ROC) curve analysis between the operated and the no-apparent laterality groups was performed using AVS parameters and loading test for diagnosis of PA. Result Agreement between image findings and AVS results was 56.3%. ROC curve analysis revealed that the lateralization index (LI) after adrenocorticotropin stimulation cutoff was 2.40, with 98.8% sensitivity and 97.1% specificity. The contralateral suppression index (CSI) cutoff value was 1.19, with 98.0% sensitivity and 93.9% specificity. All patients over the LI and CSI cutoff values exhibited unilateral subtypes. Among the loading test, the best classification accuracy was achieved using the PAC reduction rate after a saline infusion test (SIT) &gt;33.8%, which yielded 87.2% sensitivity or a PAC after a SIT &lt;87.9 pg/mL with 86.2% specificity for predicting bilateral PA. Conclusion The combined criteria of the PAC reduction rate and PAC after the SIT can determine which subset of patients with APA who should be performed AVS for validation.