PhD1

The hormone erythropoietin (Epo) maintains red blood cell mass by promoting the survival, proliferation and differentiation of erythrocytic progenitors. Circulating Epo originates mainly from fibroblasts in the renal cortex. Epo production is controlled at the transcriptional level. Hypoxia attenuates the inhibition of the Epo promoter by GATA-2. More importantly, hypoxia promotes the availability of heterodimeric (α/β) hypoxia-inducible transcription factors (predominantly HIF-2) which stimulate the Epo enhancer. The HIFs are inactivated in normoxia by enzymatic hydroxylation of their α-subunits. Three HIF-α prolyl hydroxylases (PHD-1, -2 and -3) initiate proteasomal degradation of HIF-α, while an asparaginyl hydroxylase ('factor inhibiting HIF-1', FIH-1) inhibits the transactivation potential. The HIF-α hydroxylases contain Fe(2+) and require 2-oxoglutarate as co-factor. The in vivo response is dynamic, i.e. the concentration of circulating Epo increases initially greatly following an anaemic or hypoxaemic stimulus and then declines despite continued hypoxia. Epo and angiotensin II collaborate in the maintenance of the blood volume. Whether extra-renal sites (brain, skin) modulate renal Epo production is a matter of debate. Epo overproduction results in erythrocytosis. Epo deficiency is the primary cause of the anaemia in chronic kidney disease and a contributing factor in the anaemias of chronic inflammation and cancer. Here, recombinant analogues can substitute for the hormone.

The pathogenetic mechanism of contrast-induced acute kidney injury (CI-AKI), which is the third most common cause of hospital-acquired AKI, has not been elucidated. Previously, we demonstrated that renal injury and cell apoptosis were attenuated in nlrp3 knockout CI-AKI mice. Here, we investigated the mechanism underlying NLRP3 inhibition-mediated attenuation of apoptosis in CI-AKI. The RNA sequencing analysis of renal cortex revealed that the nlrp3 or casp1 knockout CI-AKI mice exhibited upregulated cellular response to hypoxia, mitochondrial oxidation, and autophagy when compared with the wild-type (WT) CI-AKI mice, which indicated that NLRP3 inflammasome inhibition resulted in the upregulation of hypoxia signaling pathway and mitophagy. The nlrp3 or casp1 knockout CI-AKI mice and iohexol-treated HK-2 cells with MCC950 pretreatment exhibited upregulated levels of HIF1A, BECN1, BNIP3, and LC3B-II, as well as enhanced colocalization of LC3B with BNIP3 and mitochondria, and colocalization of mitochondria with lysosomes. Additionally, roxadustat, a HIF prolyl-hydroxylase inhibitor, protected the renal tubular epithelial cells against iohexol-induced injury through stabilization of HIF1A and activation of downstream BNIP3-mediated mitophagy in vivo and in vitro. Moreover, BNIP3 deficiency markedly decreased mitophagy, and also significantly exacerbated apoptosis and renal injury. This suggested the protective function of BNIP3-mediated mitophagy in CI-AKI. This study elucidated a novel mechanism in which NLRP3 inflammasome inhibition attenuated apoptosis and upregulated HIF1A and BNIP3-mediated mitophagy in CI-AKI. Additionally, this study demonstrated the potential applications of MCC950 and roxadustat in clinical CI-AKI treatment.

The hypoxia-inducible factor (HIF) co-ordinates the adaptive transcriptional response to hypoxia in metazoan cells. The hypoxic sensitivity of HIF is conferred by a family of oxygen-sensing enzymes termed HIF hydroxylases. This family consists of three prolyl hydroxylases (PHD1-3) and a single asparagine hydroxylase termed factor inhibiting HIF (FIH). It has recently become clear that HIF hydroxylases are functionally non-redundant and have discrete but overlapping physiological roles. Furthermore, altered abundance or activity of these enzymes is associated with a number of pathologies. Pharmacological HIF-hydroxylase inhibitors have recently proven to be both tolerated and therapeutically effective in patients. In this review, we focus on the physiology, pathophysiology and therapeutic potential of the PHD1 isoform, which has recently been implicated in diseases including inflammatory bowel disease, ischaemia and cancer.