Molecular mechanisms of ischemic preconditioning in the kidney

Abstract

More effective therapeutic strategies for the prevention and treatment of acute kidney injury (AKI) are needed to improve the high morbidity and mortality associated with this frequently encountered clinical condition. Ischemic and/or hypoxic preconditioning attenuates susceptibility to ischemic injury, which results from both oxygen and nutrient deprivation and accounts for most cases of AKI. While multiple signaling pathways have been implicated in renoprotection, this review will focus on oxygen-regulated cellular and molecular responses that enhance the kidney's tolerance to ischemia and promote renal repair. Central mediators of cellular adaptation to hypoxia are hypoxia-inducible factors (HIFs). HIFs play a crucial role in ischemic/hypoxic preconditioning through the reprogramming of cellular energy metabolism, and by coordinating adenosine and nitric oxide signaling with antiapoptotic, oxidative stress, and immune responses. The therapeutic potential of HIF activation for the treatment and prevention of ischemic injuries will be critically examined in this review.

Keywords: HIF prolyl-4-hydroxylases; acute kidney injury; adenosine; dioxygenases; erythropoietin; hypoxia; hypoxia-inducible factor; inflammation; ischemic preconditioning; oxygen sensing.

Fig. 1.

Overview of canonical hypoxic signaling via the prolyl-4-hydroxylase domain (PHD)/hypoxia-inducible factor (HIF) axis. Under normoxic conditions, PHD enzymes hydroxylate specific proline residues located within the oxygen-dependent degradation domain of HIF-α subunits. Prolyl-hydroxylation is required for binding to the von Hippel-Lindau (VHL)-E3 ubiquitin ligase complex, which ubiquitylates HIF-α, triggering its proteasomal degradation. When prolyl-4-hydroxylation is inhibited, e.g., in the absence of molecular oxygen or ferrous iron, HIF-α escapes degradation and translocates to the nucleus, where it dimerizes with the aryl-hydrocarbon-receptor nuclear translocator (ARNT), the constitutively expressed HIF-β subunit. HIF-α/ARNT heterodimers bind to hypoxia response element (HRE)-containing regulatory DNA sequences and increase the transcription of oxygen-regulated genes (e.g. EPO, PDK1, LDHα) through recruitment of transcriptional coactivators such as p300/CBP. Factor-inhibiting HIF (FIH), another oxygen- and iron-dependent dioxygenase, hydroxylates a specific asparagine residue located within the HIF-α COOH-terminal transactivation domain, thereby inhibiting transcriptional cofactor recruitment. HIF-α stabilization results in the activation of multiple transcriptional programs, including erythropoiesis, iron metabolism, vascular remodeling, cellular metabolism, and others.

Fig. 2.

Schematic depicting the role of the endothelial PHD/HIF-2 axis in renoprotection. Pharmacological HIF activation through HIF prolyl-4-hydroxylase inhibition (PHI) promotes recovery from renal ischemic injury via activation of endothelial HIF-2-dependent signaling and suppression of VCAM1.

Fig. 3.

Molecular mechanisms implicated in PHD/HIF-mediated renoprotection induced by ischemic/hypoxic preconditioning. HIF attenuates ischemia-reperfusion injury through coordinated activation of cytoprotective signaling pathways. Shown are oxygen-regulated biological processes and signaling pathways with key roles in PHD/HIF-mediated renoprotection. NO, nitric oxide.