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.