We hypothesized that an interplay between aryl hydrocarbon receptor (AhR) and cysteine-related thiolome at the kidney cortex underlies the mechanisms of (mal)adaptation to chronic intermittent hypoxia (CIH), promoting arterial hypertension (HTN). Using a rat model of CIH-HTN, we investigated the impact of short-term (1 and 7 days), mid-term (14 and 21 days, pre-HTN), and long-term intermittent hypoxia (IH) (up to 60 days, established HTN) on Cyp1a1 protein level (a sensitive hallmark of AhR activation) and cysteine-related thiol pools. We found that acute and chronic IH had opposite effects on Cyp1a1 and the thiolome. While short-term IH decreased Cyp1a1 and increased protein-S-thiolation, long-term IH increased Cyp1a1 and free oxidized cysteine. In addition, an in vitro administration of cystine, but not cysteine, to human endothelial cells increased Cyp1a1 expression, supporting cystine as a putative AhR activator. This study supports Cyp1a1 as a biomarker of obstructive sleep apnea (OSA) severity and oxidized pools of cysteine as risk indicator of OSA-HTN. This work contributes to a better understanding of the mechanisms underlying the phenotype of OSA-HTN, mimicked by this model, which is in line with precision medicine challenges in OSA.

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<b><i>Background:</i></b> The recent growing evidence that the proximal tubule underlies the early pathogenesis of diabetic kidney disease (DKD) is unveiling novel and promising perspectives. This pathophysiological concept links tubulointerstitial oxidative stress, inflammation, hypoxia, and fibrosis with the progression of DKD. In this new angle for DKD, the prevailing molecular mechanisms on proximal tubular cells emerge as an innovative opportunity for prevention and management of DKD as well as to improve diabetic dysmetabolism. <b><i>Summary:</i></b> The mercapturate pathway (MAP) is a classical metabolic detoxification route for xenobiotics that is emerging as an integrative circuitry detrimental to resolve tubular inflammation caused by endogenous electrophilic species. Herein we review why and how it might underlie DKD. <b><i>Key Messages:</i></b> MAP is a hallmark of proximal tubular cell function, and cysteine-<i>S</i>-conjugates might represent targets for early intervention in DKD. Moreover, the biomonitoring of urinary mercapturates from metabolic inflammation products might be relevant for the implementation of preventive/management strategies in DKD.

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The mercapturate pathway is a unique metabolic circuitry that detoxifies electrophiles upon adducts formation with glutathione. Since its discovery over a century ago, most of the knowledge on the mercapturate pathway has been provided from biomonitoring studies on environmental exposure to toxicants. However, the mercapturate pathway-related metabolites that is formed in humans—the mercapturomic profile—in health and disease is yet to be established. In this paper, we put forward the hypothesis that these metabolites are key pathophysiologic factors behind the onset and development of non-communicable chronic inflammatory diseases. This review goes from the evidence in the formation of endogenous metabolites undergoing the mercapturate pathway to the methodologies for their assessment and their association with cancer and respiratory, neurologic and cardiometabolic diseases.

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After 24 hrs, mean serum creatinine level was found 1.70AE0.48 mg/dl and 1.15AE0.20 mg/dl in group I and group II respectively. After 48 hrs, mean serum creatinine level was 2.62AE0.88 mg/dl in group I and 1.14AE0.20 mg/dl in group II. After 24 hrs and after 48 hrs, mean serum creatinine level was significantly (p<0.05) higher in group I than group II. In group I, serum creatinine level at baseline vs after 24 hrs and baseline vs after 48 hrs was statistically significant (p<0.05). Based on the Receiver Operator Characteristic (ROC) curve NGAL level had an area under curve 0.882 which gave a cut off value of $185.90 ng/ml, with 75.0% sensitivity and 100.0% specificity for prediction of AKI (Figure I). Eight patients were AKI positive among them 6 (75.0%) patients were NGAL positive and 2 (25.0%) were NGAL negative. All non AKI patients (34 patients) were NGAL negative. Negative not significant Pearson's correlation (r=-0.042; p=0.921) was found between serum creatinine level after 6 hrs with post operative NGAL in AKI patients. Positive significant Pearson's correlation was found between serum creatinine level at 24 hrs (r=0.488; p<0.05) and 48 hours (r=0.817; p=0.013) with post operative NGAL in AKI patients. Conclusions: Diagnosis of AKI was delayed by 24-48 hrs by serum creatinine measurement. This study has demonstrated that level of urinary NGAL concentration at 6 hours post CPB increased before the increase of serum creatinine level and urinary NGAL is an early predictor of AKI in adult CABG patients.