Inhibition of Endothelial PHD2 Suppresses Post-Ischemic Kidney Inflammation through Hypoxia-Inducible Factor-1

Abstract

BackgroundProlyl-4-hydroxylase domain-containing proteins 1–3 (PHD1 to PHD3) regulate the activity of the hypoxia-inducible factors (HIFs) HIF-1 and HIF-2, transcription factors that are key regulators of hypoxic vascular responses. We previously reported that deficiency of endothelial HIF-2 exacerbated renal ischemia-reperfusion injury, whereas inactivation of endothelial PHD2, the main oxygen sensor, provided renoprotection. Nevertheless, the molecular mechanisms by which endothelial PHD2 dictates AKI outcomes remain undefined.MethodsTo investigate the function of the endothelial PHD2/HIF axis in ischemic AKI, we examined the effects of endothelial-specific ablation of PHD2 in a mouse model of renal ischemia-reperfusion injury. We also interrogated the contribution of each HIF isoform by concurrent endothelial deletion of both PHD2 and HIF-1 or both PHD2 and HIF-2.ResultsEndothelial deletion of Phd2 preserved kidney function and limited transition to CKD. Mechanistically, we found that endothelial Phd2 ablation protected against renal ischemia-reperfusion injury by suppressing the expression of proinflammatory genes and recruitment of inflammatory cells in a manner that was dependent on HIF-1 but not HIF-2. Persistence of renoprotective responses after acute inducible endothelial-specific loss of Phd2 in adult mice ruled out a requirement for PHD2 signaling in hematopoietic cells. Although Phd2 inhibition was not sufficient to induce detectable HIF activity in the kidney endothelium, in vitro experiments implicated a humoral factor in the anti-inflammatory effects generated by endothelial PHD2/HIF-1 signaling.ConclusionsOur findings suggest that activation of endothelial HIF-1 signaling through PHD2 inhibition may offer a novel therapeutic approach against ischemic AKI.

Hypoxia response and acute lung and kidney injury: possible implications for therapy of COVID-19

“…During this process they undergo activation with increased expression of adhesion molecules, causing the recruitment and activation of inflammatory cells. Recently, Rajendran et al [ 43 ] investigated the effects of endothelial-specific ablation of PHD2 in a mouse model of renal ischaemia–reperfusion injury. This was found to improve early and late damages occurring during AKI, thanks to the suppression of the expression of proinflammatory genes and recruitment of inflammatory cells in a HIF-1α-dependent manner.…”

κ-opioid receptor stimulation alleviates rat vascular smooth muscle cell calcification via PFKFB3-lactate signaling

“…Hypoxia contributes to VC by inducing osteochondrogenic differentiation of VSMC in a HIF-1a–dependent and mitochondria-derived reactive oxygen species–dependent manner [ 21 ]. Of the three PHD isoforms, PHD2 appears to be the primary HIF-1a hydroxylase based on genetically engineered mice and cell culture studies [ 46 ]. In the present study, we have shown that the PHD2 regulated PFKFB3 expression in VSMCs during calcification.…”

HIF in Nephrotoxicity during Cisplatin Chemotherapy: Regulation, Function and Therapeutic Potential

“…In view of the role of HIF in cisplatin-induced nephrotoxicity, targeting or activating HIF and its related pathways may be a therapeutic strategy. PHD-pVHL pathway plays a vital role in HIF regulation, and pharmacological or genetic inhibition of PHD activity is under intensive research in kidney diseases [ 18 , 45 , 167 , 168 , 181 , 182 , 183 , 184 , 185 ]. The role of regulating HIF in cisplatin-induced nephrotoxicity is summarized in Table 1 ; besides the evidence that HIF accumulation by PHD inhibitors treatment protects against cisplatin-induced nephrotoxicity [ 18 ], studies have reported beneficial effects of PHD inhibitors in other kidney diseases including ischemic AKI [ 167 , 168 ], diabetic nephropathy [ 182 , 183 ], obesity related kidney disease [ 181 ], chronic tubulointerstitial nephritis [ 184 ], and remnant kidneys models of CKD [ 186 ].…”