Role of Endothelial Prolyl-4-Hydroxylase Domain Protein/Hypoxia-Inducible Factor Axis in Acute Kidney Injury

Abstract

Ischemia reperfusion injury (IRI) results from a cessation or restriction of blood supply to an organ followed by reestablishment of perfusion and reoxygenation. In the kidney, IRI due to transplantation, cardiac surgery with cardiopulmonary bypass, and other major vascular surgeries contributes to acute kidney injury (AKI), a clinical condition associated with significant morbidity and mortality in hospitalized patients. In the postischemic kidney, endothelial damage promotes inflammatory responses and leads to persistent hypoxia of the renal tubular epithelium. Like other cell types, endothelial cells respond to low oxygen tension by multiple hypoxic signaling mechanisms. Key mediators of adaptation to hypoxia are hypoxia-inducible factors (HIF)-1 and -2, transcription factors whose activity is negatively regulated by prolyl-hydroxylase domain proteins 1 to 3 (PHD1 to PHD3). The PHD/HIF axis controls several processes determining injury outcome, including ATP generation, cell survival, proliferation, and angiogenesis. Here, we discuss recent advances in our understanding of the endothelial-derived PHD/HIF signaling and its effects on postischemic AKI.

Renal hypoxia–HIF–PHD–EPO signaling in transition metal nephrotoxicity: friend or foe?

“…Modulation of the different components of HPHE signaling may also be advocated using pharmacological PHD inhibitors (PHIs) to induce endogenous defense mechanisms, as described with “hypoxic preconditioning” for various causes of AKI and CKD, including TMs (reviewed in Shu et al 2019 ; Tanaka 2016 ; Tiwari and Kapitsinou 2021 ); see also “ General considerations ” in “ Impact of toxic metal ions on the renal HPHE signaling axis ”). PHIs are specific drugs that activate HPHE signaling and were developed to stimulate the production of endogenous EPO in anemia of CKD (Haase 2021 ).…”

“…However, regarding therapy of acute versus chronic TM-induced nephrotoxicity a more differentiated approach and a note of caution are necessary. In TM-induced AKI, the literature suggests that PHIs could be useful to increase survival and nephroprotection (reviewed in Li et al 2021 ; Shu et al 2019 ; Tiwari and Kapitsinou 2021 ). In contrast, therapeutic application of PHIs for CKD induced by TM ions may be a double-edged sword, first because of the putative proapoptotic (reviewed in Mazure and Pouyssegur 2010 ; Piret et al 2002 ) and pro-fibrotic potential of HPHE activation, due to the interdependence between inflammatory (e.g.…”

Protective effects of MSC-conditioned medium on DFO-induced mimetic-hypoxia injury of renal tubular epithelial cells

“…But it's still controversial whether HIF-1α promotes or inhibits renal injury and renal brosis. On one hand, some studies indicated that HIF-1 might improve cells' tolerance to conditions of hypoxia, thus reducing the apoptosis of renal cell, promoting the repair of acute renal tubular necrosis and nally protecting kidney from AKI [5,18]. For example, Yang et al [48] found that in cisplatin-induced AKI model of mice, HK2 cells and mouse proximal tubular cells (mPTCs), HIF-1α, activated by FG-4592 as a PHD inhibitor before modeling, could signi cantly inhibit the up-regulation of BUN, Cr, cystatin C, Kim-1 as well as NGAL, inhibit cell apoptosis and improve cisplatin-induced renal injury.…”

“…Once AKI occurs, the surviving RTECs regenerate and repair; normal repair can restore the integrity of renal tubules, but maladaptive or incomplete repair can result in the occurrence of epithelial-mesenchymal transition (EMT) and ECM deposition, promoting renal brosis and eventually leading to CKD or ESRD [3,4]. In AKI caused by different conditions, hypoxia is a key driver contributing to the death and injury of RTECs [5]. And AKI still remains a worldwide public health problem because of its rising morbidity, signi cant mortality and lack of speci c targeted treatment [4,6].…”

Endogenous humoral determinants of vascular endothelial dysfunction as triggers of acute poisoning complications

“…Additionally, the activity of endothelin‐1 is increased in hypoxia (Siques et al, 2021). VE dysfunction also underlies the hypoxic disruption of dilatory capacity in non‐pulmonary blood vessels (Jones et al, 2021) and of the blood–brain barrier (BBB) (Baumann et al, 2022) and renal tubular epithelium (Tiwari & Kapitsinou, 2021).…”