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Hypoxic preconditioning protects against ischemic kidney injury through the IDO1/kynurenine pathway.

ABSTRACT: Prolonged cellular hypoxia leads to energetic failure and death. However, sublethal hypoxia can trigger an adaptive response called hypoxic preconditioning. While prolyl-hydroxylase (PHD) enzymes and hypoxia-inducible factors (HIFs) have been identified as key elements of oxygen-sensing machinery, the mechanisms by which hypoxic preconditioning protects against insults remain unclear. Here, we perform serum metabolomic profiling to assess alterations induced by two potent cytoprotective approaches, hypoxic preconditioning and pharmacologic PHD inhibition. We discover that both approaches increase serum kynurenine levels and enhance kynurenine biotransformation, leading to preservation of NAD⁺ in the post-ischemic kidney. Furthermore, we show that indoleamine 2,3-dioxygenase 1 (Ido1) deficiency abolishes the systemic increase of kynurenine and the subsequent renoprotection generated by hypoxic preconditioning and PHD inhibition. Importantly, exogenous administration of kynurenine restores the hypoxic preconditioning in the context of Ido1 deficiency. Collectively, our findings demonstrate a critical role of the IDO1-kynurenine axis in mediating hypoxic preconditioning.

SUBMITTER: Torosyan R

PROVIDER: S-EPMC8487442 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundUremic cardiomyopathy is a common cardiovascular complication of chronic kidney disease (CKD) characterized by left ventricular hypertrophy (LVH) and fibrosis enhancing the susceptibility of the heart to acute myocardial infarction. In the early stages of CKD, approximately 60% of patients are women. We aimed to investigate the influence of sex on the severity of uremic cardiomyopathy and the infarct size-limiting effect of ischemic preconditioning (IPRE) in experimental CKD.MethodsCKD was induced by 5/6 nephrectomy in 9-week-old male and female Wistar rats. Two months later, serum and urine laboratory parameters were measured to verify the development of CKD. Transthoracic echocardiography was performed to assess cardiac function and morphology. Cardiomyocyte hypertrophy and fibrosis were measured by histology. Left ventricular expression of A- and B-type natriuretic peptides (ANP and BNP) were measured by qRT-PCR and circulating BNP level was measured by ELISA. In a subgroup of animals, hearts were perfused according to Langendorff and were subjected to 35 min global ischemia and 120 min reperfusion with or without IPRE (3 × 5 min I/R cycles applied before index ischemia). Then infarct size or phosphorylated and total forms of proteins related to the cardioprotective RISK (AKT, ERK1,2) and SAFE (STAT3) pathways were measured by Western blot.ResultsThe severity of CKD was similar in males and females. However, CKD males developed more severe LVH compared to females as assessed by echocardiography. Histology revealed cardiac fibrosis only in males in CKD. LV ANP expression was significantly increased due to CKD in both sexes, however, LV BNP and circulating BNP levels failed to significantly increase in CKD. In both sexes, IPRE significantly decreased the infarct size in both the sham-operated and CKD groups. IPRE significantly increased the phospho-STAT3/STAT3 ratio in sham-operated but not in CKD animals in both sexes. There were no significant differences in phospho-AKT/AKT and phospho-ERK1,2/ERK1,2 ratios between the groups.ConclusionThe infarct size-limiting effect of IPRE was preserved in both sexes in CKD despite the more severe uremic cardiomyopathy in male CKD rats. Further research is needed to identify crucial molecular mechanisms in the cardioprotective effect of IPRE in CKD.

Project description:Sepsis is a common and life-threatening systemic disorder, often leading to acute injury of multiple organs. Here, we show that remote ischemic preconditioning (rIPC), elicited by brief episodes of ischemia and reperfusion in femoral arteries, provides protective effects against sepsis-induced acute kidney injury (AKI). Methods: Limb rIPC was conducted on mice in vivo 24 h before the onset of cecal ligation and puncture (CLP), and serum exosomes derived from rIPC mice were infused into CLP-challenged recipients. In vitro, we extracted and identified exosomes from differentiated C2C12 cells (myotubes) subjected to hypoxia and reoxygenation (H/R) preconditioning, and the exosomes were administered to lipopolysaccharide (LPS)-treated mouse tubular epithelial cells (mTECs) or intravenously injected into CLP-challenged miR-21 knockout mice for rescue experiments. Results: Limb rIPC protected polymicrobial septic mice from multiple organ dysfunction, systemic accumulation of inflammatory cytokines and accelerated parenchymal cell apoptosis through upregulation of miR-21 in a hypoxia-inducible factor 1? (HIF-1?)-dependent manner in the ischemic limbs of mice. However, in miR-21 knockout mice or mice that received HIF-1? siRNA injection into hind limb muscles, the organ protection conferred by limb rIPC was abolished. Mechanistically, we discovered that miR-21 was transported from preischemic limbs to remote organs via serum exosomes. In kidneys, the enhanced exosomal miR-21 derived from cultured myotubes with H/R or the serum of mice treated with rIPC integrated into renal tubular epithelial cells and then targeted the downstream PDCD4/NF-?B and PTEN/AKT pathways, exerting anti-inflammatory and anti-apoptotic effects and consequently attenuating sepsis-induced renal injury both in vivo and in vitro. Conclusion: This study demonstrates a critical role for exosomal miR-21 in renoprotection conferred by limb rIPC against sepsis and suggests that rIPC and exosomes might serve as the possible therapeutic strategies for sepsis-induced kidney injury.

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Hypoxic preconditioning protects against ischemic kidney injury through the IDO1/kynurenine pathway.

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