The Circadian Clock Regulates the Expression of the Nuclear Factor Erythroid 2-Related Factor 2 in Acute Kidney Injury following Myocardial Ischemia-Reperfusion in Diabetic Rat

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Abstract

Cardiac surgery-associated acute kidney injury (AKI) is a serious and frequent complication with poor prognosis, and disruption in circadian rhythm shall adversely influence cardiovascular and renal functions via oxidative stress mechanisms. However, the role of circadian clock genes (circadian locomotor output cycle kaput (CLOCK) and brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein-1 (BMAL1)) and its interaction with nuclear factor erythroid 2-related factor 2 (Nrf2) in AKI following myocardial ischemia-reperfusion (MIR) in the diabetic rat has not yet been explored. In this study, rats were divided into the sham (S) group, MIR (M) group, diabetic (D) group, and diabetic+MIR (DM) group. At light (zeitgeber time (ZT) 0) and dark time points (ZT12), rat MIR model was established by occlusion of the left anterior descending coronary artery for 30 min followed by 2 -hour reperfusion, and then renal injury was evaluated. The renal histological changes in the DM group were significantly high compared to other groups; serum creatinine, blood urea nitrogen, and neutrophil gelatinase-associated lipocalin levels, as well as malondialdehyde and 8-iso-prostaglandin-F2α levels in renal tissues of M ZT12 and DM ZT12 subgroups, were significantly higher than those of M ZT0 and DM ZT0 subgroups, individually indicating increased oxidative stress at a dark cycle. Further, Nrf2 protein accumulated in a circadian manner with decreasing levels at night in the DM and M groups. In conclusion, renal injury following MIR was exacerbated in the diabetic rat at night through molecular mechanisms involving transcriptional control of the circadian clock on light-dark activation of Nrf2.

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Neutrophil gelatinase-associated lipocalin (NGAL): a promising biomarker for the early diagnosis of acute kidney injury (AKI).

Elio Antonucci, Giuseppe Lippi, Andrea Ticinesi … (2014)

Acute kidney injury (AKI) is a common complication that occurs in a broad spectrum of clinical settings. Cardiac surgery-associated AKI continues to be a well-recognized complication of cardiac surgery with high morbidity and mortality. The lack of early biomarkers has for long prevented timely interventions to mitigate the effects of AKI. Serum creatinine is not a timely marker of AKI, so that it cannot be used to set potentially effective therapies to treat AKI in patients during phases when the injury is still potentially reversible. Neutrophil gelatinase-associated lipocalin (NGAL) has been identified as a promising biomarker for early detection of AKI. Several studies have shown that NGAL levels significantly increase in AKI patients 24 to 48 hours before a detectable increase of serum creatinine. Recent studies also suggest that measurements of urinary NGAL levels in patients at risk for cardiac surgery-associated AKI may facilitate its early diagnosis and allow clinicians to implement therapeutic adjustments that have the potential to reverse renal cellular damage and minimize further kidney injury.