Significance Statement Cells undergoing necrosis release extracellular high mobility group box (HMGB)-1, which triggers sterile inflammation upon AKI in mice. Neither deletion of HMGB1 from tubular epithelial cells, nor HMGB1 antagonism with small molecules, affects initial ischemic tubular necrosis and immediate GFR loss upon unilateral ischemia/reperfusion injury (IRI). On the contrary, tubular cell-specific HMGB1 deficiency, and even late-onset pharmacological HMGB1 inhibition, increased functional and structural recovery from AKI, indicating that intracellular HMGB1 partially counters the effects of extracellular HMGB1. In vitro studies indicate that intracellular HMGB1 decreases resilience of tubular cells from prolonged ischemic stress, as in unilateral IRI. Intracellular HMGB1 is a potential target to enhance kidney regeneration and to improve long-term prognosis in AKI. Background Late diagnosis is a hurdle for treatment of AKI, but targeting AKI-CKD transition may improve outcomes. High mobility group box-1 (HMGB1) is a nuclear regulator of transcription and a driver of necroinflammation in AKI. We hypothesized that HMGB1 would also modulate AKI-CKD transition in other ways. Methods We conducted single-cell transcriptome analysis of human and mouse AKI and mouse in vivo and in vitro studies with tubular cell-specific depletion of Hmgb1 and HMGB1 antagonists. Results HMGB1 was ubiquitously expressed in kidney cells. Preemptive HMGB1 antagonism with glycyrrhizic acid (Gly) and ethyl pyruvate (EP) did not affect postischemic AKI but attenuated AKI-CKD transition in a model of persistent kidney hypoxia. Consistently, tubular Hmgb1 depletion in Pax8 rtTA, TetO Cre, Hmgb1 fl/fl mice did not protect from AKI, but from AKI-CKD transition. In vitro studies confirmed that absence of HMGB1 or HMGB1 inhibition with Gly and EP does not affect ischemic necrosis of growth-arrested differentiated tubular cells but increased the resilience of cycling tubular cells that survived the acute injury to oxidative stress. This effect persisted when neutralizing extracellular HMGB1 with 2G7. Consistently, late-onset HMGB1 blockade with EP started after the peak of ischemic AKI in mice prevented AKI-CKD transition, even when 2G7 blocked extracellular HMGB1. Conclusion Treatment of AKI could become feasible when (1) focusing on long-term outcomes of AKI; (2) targeting AKI-CKD transition with drugs initiated after the AKI peak; and (3) targeting with drugs that block HMGB1 in intracellular and extracellular compartments.
BackgroundZinc is an essential trace element involved in multiple metabolic processes. Acute kidney injury (AKI) is associated with low plasma zinc, but outcomes with zinc supplementation in critically ill patients with AKI remain unknown. Our objective was to investigate the effectiveness of zinc supplementation in this patient population.MethodsCritically ill patients with AKI were identified from the Medical Informative Mart for Intensive Care IV database. Prosperity score matching (PSM) was applied to match patients receiving zinc treatment to those without zinc treatment. The association between zinc sulfate use and in-hospital mortality and 30-day mortality, need for renal replacement therapy (RRT), and length of stay was determined by logistic regression and Cox proportional hazards modeling.ResultsA total of 9,811 AKI patients were included in the study. PSM yielded 222 pairs of patients who received zinc treatment and those who did not. Zinc supplementation was associated with reduced in-hospital mortality (HR = 0.48 (95% CI: 0.28, 0.83) P = 0.009) and 30-day mortality (HR = 0.51 (95% CI, 0.30, 0.86) P = 0.012). In the subgroup analysis, zinc use was associated with reduced in-hospital mortality in patients with stage 1 AKI and those with sepsis.ConclusionsZinc supplementation was associated with improved survival in critically ill patients with AKI. The supplementation was especially effective in those with stage 1 AKI and sepsis. These results need to be verified in randomized controlled trials.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.