IntroductionThe hypoxia-inducible factor (HIF) pathway plays a protective role in regulating genes that mitigate the effects of low oxygen tension. Under normoxic conditions, oxygen-sensitive HIF-␣ isoforms are rendered inactive via proline hydroxylation by HIF-specific prolyl hydroxylases (HIF-PHs), which lead to binding of von HippelLindau protein and targeted degradation through the ubiquitinproteasome pathway. Under hypoxic conditions, where less oxygen substrate is available for proline hydroxylation by HIF-PHs, HIF-␣ isoforms are stabilized, heterodimerize with HIF-␤, and translocate to the nucleus where they bind to hypoxia-responsive element (HRE) motifs. [1][2][3] In cooperation with other transcriptional coactivators, HIF induces transcription of genes that ameliorate the effects of hypoxia, including EPO and its receptor, transferrin and its receptor, glucose transporters and glycolytic enzymes, and vascular endothelial growth factor (VEGF). 4 A relationship between fetal hemoglobin (HbF) levels and hypoxia has been reported for nearly half a century: increased HbF levels are associated with intrauterine hypoxia, 5 maternal smoking, 6 postnatal hypoxemia from congenital heart disease, 7,8 and anemia of prematurity. 9 Additionally, infants born at high altitude demonstrate enhanced erythropoiesis and elevated HbF levels compared with infants born at sea level. 10 Evidence for postnatal induction of HbF through a hypoxia pathway also exists in several species. Camelids adapt to hypoxia through increased fetal hemoglobin levels, with adult alpacas demonstrating HbF levels of 55% at high altitude. 11 In young baboons, significant increases in HbF levels occurred after phenylhydrazine induced hemolysis or hypobaric hypoxia. 12 While the magnitude of the HbF response may be genetically determined, 13 HbF levels could be maintained longterm by continued erythropoietic stress. 14 Indeed, a relationship between the HIF pathway and HbF expression has been proposed recently, and putative HIF-binding sites have been described in the locus control region of the globin gene cluster. 15 Thus modulating HIF-␣, the critical and labile subunit(s) in the HIF pathway orchestrating the response to hypoxia, represents a new direction to investigate for HbF induction.Stabilization of HIF-␣ through inhibition of HIF-PHs may have therapeutic potential in the treatment of the ␤-hemoglobinopathies. For example, the hypoxic environment during fetal development is protective for individuals with sickle cell anemia; however, following the transition to normoxia at birth, fetal hemoglobin levels fall with a gradual replacement of the ␥-globin chain by the abnormal ␤-globin chain, rendering the pathologic hemoglobin (Hb) tetramer prone to polymerization upon deoxygenation. The polymerized Hb leads to impaired deformability and sickling of red blood cells, which lodge in end arterioles, producing the classic and most prominent feature of the disorder, repeated vasoocclusive crises. Individuals who coinherit mutations resulting in her...

Summary Exercise‐induced pulmonary haemorrhage (EIPH) causes serious economic losses in the horse racing industry. Endoscopic examination indicates that 40–90% of horses exhibit EIPH following sprint exercise, but the limitations of the endoscope prevent diagnosis in many horses. Bronchoalveolar lavage (BAL) was utilised to detect red blood cells (RBCs) in the terminal airways in 6 horses. Two lavages were performed at weekly intervals prior to exercise, one within 90 min after exercise, and 5 at weekly intervals after exercise. The horses were exercised strenuously at 12.5–14.6 m/s on a treadmill (3 degree incline). Heart rates ranged from 192–207 beats/min, and mean pulmonary arterial pressures (mPAP) ranged from 80–102 mmHg. Neither epistaxis nor endoscopic evidence of EIPH was seen in any of the 6 horses following exercise. However, the number of RBCs in the lavage fluid increased significantly over control values immediately after exercise in all horses but returned to control values by one week after exercise. Haemosiderophages in the BAL fluid did not increase until one week after exercise and remained elevated for 3 weeks after exercise. Twenty per cent of the total population of alveolar macrophages contained haemosiderin. A positive relationship occurred between the number of RBCs in the lavage fluid and mPAP; the amount of haemorrhage increased as the mPAP exceeded 80 to 90 mmHg. The results with BAL used as the diagnostic tool, suggest that all strenuously exercised horses may exhibit EIPH; the amount of haemorrhage appears to be associated with the magnitude of the high pulmonary arterial pressure.

Hypoxia-inducible factor (HIF) prolyl 4-hydroxylases are a family of iron-and 2-oxoglutarate-dependent dioxygenases that negatively regulate the stability of several proteins that have established roles in adaptation to hypoxic or oxidative stress. These proteins include the transcriptional activators HIF-1␣ and HIF-2␣. The ability of the inhibitors of HIF prolyl 4-hydroxylases to stabilize proteins involved in adaptation in neurons and to prevent neuronal injury remains unclear. We reported that structurally diverse low molecular weight or peptide inhibitors of the HIF prolyl 4-hydroxylases stabilize HIF-1␣ and up-regulate HIF-dependent target genes (e.g. enolase, p21 waf1/cip1 , vascular endothelial growth factor, or erythropoietin) in embryonic cortical neurons in vitro or in adult rat brains in vivo. We also showed that structurally diverse HIF prolyl 4-hydroxylase inhibitors prevent oxidative death in vitro and ischemic injury in vivo. Taken together these findings identified low molecular weight and peptide HIF prolyl 4-hydroxylase inhibitors as novel neurological therapeutics for stroke as well as other diseases associated with oxidative stress.Iron maintains a unique role in physiology via its ability to change readily its oxidation state in response to changes in its local environment. A general simplification of its primary function is that it mediates one-electron redox reactions. This chemical property of iron enables it to act as an essential component in several biological activities, including as a cofactor for enzymes such as tyrosine hydroxylase. Oxygen binding to biomolecules such as hemoglobin and myoglobin is also coordinated by iron. Indeed iron deficiency can lead to a host of disorders, including anemia and restless legs syndrome (1).Paradoxically, the biochemical properties that make iron beneficial in many biological processes appear to be a drawback when the balance between its accumulation/sequestration within cellular compartments and its release is disturbed in favor of iron accumulation (2). Indeed, iron overload is associated with several neurological conditions (3-5). For example, the iron content of nigral Lewy bodies is elevated in patients with Parkinson disease (6 -9). Alzheimer disease has also been found to be associated with an increase in the iron content of senile plaques (10 -15). Accumulation of mitochondrial iron has been shown to play a role in Friedrich ataxia (16,17). Similarly, changes in intracellular free iron levels have been observed in cerebral ischemia (18 -20). Direct evidence that disrupted iron homeostasis contributes to injury rather than simply being caused by it has been obtained by treatment with low molecular weight iron chelators or by overexpression of iron storage proteins. Small molecule iron chelators such as deferoxamine mesylate (DFO) 2 inhibit neuronal injury in rodent models of stroke (21), Parkinson disease (22), and multiple sclerosis (23). Moreover, DFO and some other metal chelators such as clioquinol have been shown to slow the progressi...

In CKD, phosphate retention arising from diminished GFR is a key early step in a pathologic cascade leading to hyperthyroidism, metabolic bone disease, vascular calcification, and cardiovascular mortality. Tenapanor, a minimally systemically available inhibitor of the intestinal sodium-hydrogen exchanger 3, is being evaluated in clinical trials for its potential to (1) lower gastrointestinal sodium absorption, (2) improve fluid overload-related symptoms, such as hypertension and proteinuria, in patients with CKD, and (3) reduce interdialytic weight gain and intradialytic hypotension in ESRD. Here, we report the effects of tenapanor on dietary phosphorous absorption. Oral administration of tenapanor or other intestinal sodiumhydrogen exchanger 3 inhibitors increased fecal phosphorus, decreased urine phosphorus excretion, and reduced [ 33 P]orthophosphate uptake in rats. In a rat model of CKD and vascular calcification, tenapanor reduced sodium and phosphorus absorption and significantly decreased ectopic calcification, serum creatinine and serum phosphorus levels, circulating phosphaturic hormone fibroblast growth factor-23 levels, and heart mass. These results indicate that tenapanor is an effective inhibitor of dietary phosphorus absorption and suggest a new approach to phosphate management in renal disease and associated mineral disorders.

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