Novel therapeutic approaches against oxidative stress and hypoxia, targeting intracellular sensor molecules for oxygenand oxidative stress

Miyata, Toshio;Van Ypersele de Strihou, Charles
(2011) Studies on Renal Disorders Studies on Renal Disorders — ISBN: [978-1-60761-856-0], p. 633-656, published

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  • Miyata, Toshio
    Author
  • Van Ypersele de Strihou, CharlesUCLouvain
    Author
Abstract
Besides hemodynamic and metabolic abnormalities, a broad derangement of oxygen metabolism, such as hypoxia and oxidative stress, has been implicated in the genesis of diabetic kidney lesions. It further impacts on various biological reactions linked to oxygen metabolism (e.g., nitrosative stress, advanced glycation, carbonyl stress, endoplasmic reticulum (ER) stress). The causal role of an impaired oxygen metabolism in diabetic kidney lesions renovates our understanding of current therapeutic benefits accruing from antihypertensive agents, the control of hyperglycemia or hyperinsulinemia, and the dietary correction of obesity. The cellular defense mechanisms against hypoxia and oxidative stress have been recently explored. The hypoxia-inducible factor (HIF) plays a key role to the defense against hypoxia. Its activity is modulated by intracellular oxygen sensors, prolylhydroxylases (PHDs). Small molecular PHD inhibitors improve kidney lesions in several animal models, including diabetic nephropathy. PHD has three isoforms whose respective roles have been delineated in mice by the specific disruption of each PHD gene. Unfortunately, no current inhibitor is specific for a distinct PHD isoform. Nonspecific inhibition of PHDs may induce adverse effects associated with PHD2 inhibition (e.g., angiogenesis). Specific disruption of the PHD1 gene induces hypoxic tolerance, without angiogenesis and erythrocytosis, through the reprogramming of basal oxygen metabolism and an attendant decreased oxidative stress in hypoxic mitochondria.Aspecific PHD1 inhibitor might therefore offer a novel therapy against hypoxia. On the other hand, transcriptional factor Nrf2 regulates the basal and inducible expressions of numerous antioxidant stress genes. Disruption of the Nrf 2 gene exacerbates oxidative renal injury. Nrf2 activity is modulated by Keap1, an intracellular sensor for oxidative stress. Inhibitors of Keap1 may thus prove therapeutic against oxixative tissue injury. Altogether, newer approaches targeting intracellular sensor for oxygen and oxidative stress may offer clinical benefits not only in the diabetic kidney but also in several diseases in which hypoxia or oxidative stress is a final, common pathway
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Miyata, T., & Van Ypersele de Strihou, C. (2011). Novel therapeutic approaches against oxidative stress and hypoxia, targeting intracellular sensor molecules for oxygenand oxidative stress. In Miyata, Toshio (ed.), Studies on Renal Disorders Studies on Renal Disorders (p. p. 633-656). Springer Science+Business Media. https://hdl.handle.net/2078.5/159323