title: Diabetic nephropathy: are there new and potentially promising therapies targeting oxygen biology?
abstract: The multipronged drug approach targeting blood pressure and serum levels of glucose, insulin, and lipids fails to fully prevent diabetic nephropathy (DN). Recently, a broad range of anomalies associated with oxygen biology, such as hypoxia, oxidative stress (OS), and dyserythropoiesis, have been implicated in DN. This review delineates the cellular mechanisms of these anomalies to pinpoint novel therapeutic approaches. The PHD-HIF system mitigates hypoxia: HIF activates a broad range of reactions against hypoxia whereas PHD is an intracellular oxygen sensor negatively regulating HIF. The Keap1-Nrf2 system mitigates OS: Nrf2 activates cellular reactions against OS whereas Keap1 negatively regulates Nrf2. Clinical trials of PHD inhibitors to correct anemia in patients with CKD as well as of a Nrf2 activator, bardoxolone methyl, for DN are under way, even if the latter has been recently interrupted. A specific PHD1 inhibitor, a Keap1 inhibitor, and an allosteric effector of hemoglobin may offer alternative, novel therapies. Erythropoietin (EPO) is critical for the development of erythroid progenitors and thus for tissue oxygen supply. Renal EPO-producing (REP) cells, originating from neural crests, but not fibroblasts from injured tubular epithelial cells, transdifferentiate into myofibroblasts and contribute to renal fibrosis. Agents restoring the initial function of REP cells might retard renal fibrosis. These newer approaches targeting oxygen biology may offer new treatments not only for DN but also for several diseases in which hypoxia and/or OS is a final, common pathway.
authors.affiliation: United Centers for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyata
authors.forename: Norio
authors.initials: N
authors.lastname: Suzuki
authors.forename: Charles
authors.initials: C
authors.lastname: van Ypersele de Strihou
mesh_terms: D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy*; D004921:Erythropoietin / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D010100:Oxygen / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D051793:Hypoxia-Inducible Factor 1; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D004921:Erythropoietin; C447780:EGLN2 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D010100:Oxygen