Caloric restriction reduces the pro-inflammatory eicosanoid 20-hydroxyeicosatetraenoic acid to protect from acute kidney injury

热量理论 急性肾损伤 医学 缺血 内科学 内分泌学 炎症 氧化应激 再灌注损伤
作者
Karla Johanna Ruth Hoyer-Allo,Martin R. Späth,Susanne Brodesser,Yiyi Zhu,Julia Binz-Lotter,Martin Höhne,Hella S. Brönneke,Katrin Bohl,Marc Johnsen,Torsten Kubacki,Katharina Kiefer,Lisa Seufert,Felix C. Koehler,Franziska Grundmann,Matthias J. Hackl,Bernhard Schermer,Jens C. Brüning,Thomas Benzing,Volker Burst,Roman‐Ulrich Müller
出处
期刊:Kidney International [Elsevier BV]
卷期号:102 (3): 560-576 被引量:10
标识
DOI:10.1016/j.kint.2022.04.033
摘要

Acute kidney injury is a frequent complication in the clinical setting and associated with significant morbidity and mortality. Preconditioning with short-term caloric restriction is highly protective against kidney injury in rodent ischemia reperfusion injury models. However, the underlying mechanisms are unknown hampering clinical translation. Here, we examined the molecular basis of caloric restriction–mediated protection to elucidate the principles of kidney stress resistance. Analysis of an RNAseq dataset after caloric restriction identified Cyp4a12a, a cytochrome exclusively expressed in male mice, to be strongly downregulated after caloric restriction. Kidney ischemia reperfusion injury robustly induced acute kidney injury in male mice and this damage could be markedly attenuated by pretreatment with caloric restriction. In females, damage was significantly less pronounced and preconditioning with caloric restriction had only little effect. Tissue concentrations of the metabolic product of Cyp4a12a, 20-hydroxyeicosatetraenoic acid (20-HETE), were found to be significantly reduced by caloric restriction. Conversely, intraperitoneal supplementation of 20-HETE in preconditioned males partly abrogated the protective potential of caloric restriction. Interestingly, this effect was accompanied by a partial reversal of caloric restriction––induced changes in protein but not RNA expression pointing towards inflammation, endoplasmic reticulum stress and lipid metabolism. Thus, our findings provide an insight into the mechanisms underlying kidney protection by caloric restriction. Hence, understanding the mediators of preconditioning is an important prerequisite for moving towards translation to the clinical setting. Acute kidney injury is a frequent complication in the clinical setting and associated with significant morbidity and mortality. Preconditioning with short-term caloric restriction is highly protective against kidney injury in rodent ischemia reperfusion injury models. However, the underlying mechanisms are unknown hampering clinical translation. Here, we examined the molecular basis of caloric restriction–mediated protection to elucidate the principles of kidney stress resistance. Analysis of an RNAseq dataset after caloric restriction identified Cyp4a12a, a cytochrome exclusively expressed in male mice, to be strongly downregulated after caloric restriction. Kidney ischemia reperfusion injury robustly induced acute kidney injury in male mice and this damage could be markedly attenuated by pretreatment with caloric restriction. In females, damage was significantly less pronounced and preconditioning with caloric restriction had only little effect. Tissue concentrations of the metabolic product of Cyp4a12a, 20-hydroxyeicosatetraenoic acid (20-HETE), were found to be significantly reduced by caloric restriction. Conversely, intraperitoneal supplementation of 20-HETE in preconditioned males partly abrogated the protective potential of caloric restriction. Interestingly, this effect was accompanied by a partial reversal of caloric restriction––induced changes in protein but not RNA expression pointing towards inflammation, endoplasmic reticulum stress and lipid metabolism. Thus, our findings provide an insight into the mechanisms underlying kidney protection by caloric restriction. Hence, understanding the mediators of preconditioning is an important prerequisite for moving towards translation to the clinical setting. In This IssueKidney InternationalVol. 102Issue 3PreviewGorski et al. meta-analyzed genome-wide association studies that covered 343,339 individuals to uncover top-priority genes responsible for progressive decline in estimated glomerular filtration rate (eGFR). This analysis identified 12 variants across 11 loci significant for annual decline in eGFR, and 9 variants that were important in analyses adjusted or unadjusted for baseline glomerular filtration rate. The effects of these variants were magnified 2- to 4-fold in patients with diabetes or chronic kidney disease (CKD) at baseline. Full-Text PDF
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