Inducing a Visceral Organ to Protect a Peripheral Capillary Bed

Serine and 1-carbon metabolism are required for HIF-mediated protection against retinopathy of prematurity

“…DMOG, unlike RXD, targets only the liver and cannot reach the retina. These data support the observation that systemic HIF-1 stabilization by DMOG protects only the wild-type mouse from oxygen toxicity but does not protect the hepatic HIF-1-KO (25). We therefore next used the hepatic HIF-1-KO mice treated with DMOG to test whether metabolites of 1CM were reduced in the hepatic HIF-1-KO.…”

“…To ensure that we were analyzing only the hepatic contribution to increases in retinal serine, we used dimethyloxalylglycine (DMOG), a widely studied α-KG antagonist and nonselective inhibitor of HIF PHD. We have definitively demonstrated that DMOG can protect only the wild-type mouse but not the hepatic HIF-1-KO, demonstrating the HIF-1 dependence of the liver to eye protection using DMOG (25). The liver selectivity of DMOG is likely a consequence of DMOG's instability and inability to survive intact after a first pass through the liver.…”

“…WT C57BL/6J mice were supplied by the Jackson Laboratory. OIR model was based on the previously described procedure developed by Smith (49) and was described in detail elsewhere (50)(51)(52). Briefly, newborn pups with their nursing dam were subjected to 75% oxygen in the Biospherix animal hyperoxia system (Biospherix Ltd.) from P7 to P12.…”

“…Transcriptional and knockout studies of animals treated with PHD inhibition have determined a unique liver-eye and liver-heart axis that directs "remote" protection against OIR and cardiac ischemia, respectively (25,26). Here we used untargeted metabolite profiling to demonstrate that (a) retinal serine/ glycine concentrations and (b) activation of retinal serine/1-carbon metabolism (1CM) are hepatic HIF-1 dependent.…”

Systems Pharmacology Links GPCRs with Retinal Degenerative Disorders

“…Sears and colleagues (62) recently identified a novel interplay between peripheral and visceral organs. These authors showed that treatments targeting the liver in mice can also prevent oxygen-induced retinopathy by altering the peripheral capillary bed of the retina.…”