The magic mountain or death in Venice: chronic hypoxia may alleviate oxidative stress in the kidney

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Chronic hypoxia, as induced by simulated high altitude at 5500 m, seems to have astonishing beneficial effects when it comes to oxidative stress. In this issue of The Journal of Physiology, Yang et al. (2007) induced lipopolysaccharide-induced oxidative stress (LPS-OS) in rats maintained at sea level and in rats being kept for 15 days in an altitude chamber. This is an original way of preconditioning the kidney.

Renal preconditioning is an area of increasing interest. It refers to the prospect of rendering the kidney resistant to subsequent injury by a prior insult manoeuvre. Ischaemic preconditioning of the kidney has been commonly used and provides protection against a subsequent ischaemic attack. Several candidates that could potentially serve as mediators of preconditioning have been identified. Yang et al. (2007) focus on the formation of superoxide by two major oxidative enzymes, NAD(P)H oxidase and xanthine oxidase, and the authors examine two antioxidative superoxide dismutase isoforms, Cu/ZnSOD and MnSOD.

The impact of chronic hypoxia on the outcome of LPS-OS on renal haemodynamics and excretory functions was remarkably clear. Non-preconditioned rats (sea level) responded to LPS-OS with pronounced reduction of renal blood flow (RBF) and glomerular filtration rate (GFR). In contrast, RBF and GFR in preconditioned rats (altitude chamber) were far less impaired. Moreover, urine and sodium excretion were significantly reduced in the rats kept at sea level, whereas this drop was not found in the rats housed in high altitude chambers. The reasons for the differences may be of pre-renal origin, since mean arterial blood pressure drops by roughly 30 mmHg in the sea level group, whereas the pressure drop in the preconditioned animals was only roughly 10 mmHg. Autoregulation of RBF and GFR may not be as pronounced as normal (Flemming et al. 2001) in this setting, and therefore these measures may drop in response to decreases in perfusion pressure. Moreover, diuresis as well as natriuresis are extremely pressure dependent (Seeliger et al. 2001).

A pre-renal origin of LPS-OS has been suggested before. Cohen et al. (2001) showed that haemodynamic changes after LPS-OS are only found in vivo, not in the isolated perfused kidney. However, in the highlighted study by Yang et al. evidence is provided for additional intrarenal effects of LPS-OS. It seems that lipopolysaccharides cause cytokine release via Toll-like receptor 4 (TLR4) (Cunningham et al. 2004), a receptor exclusively located in the kidney. Not only is TLR4 restricted to the kidney, it is also known to stimulate tumour necrosis factor-α, and interleukin-β production, resulting in NAD(P)H-oxidase generated superoxide (Li et al. 2002). Indeed, Yang et al. could demonstrate increased renal superoxide formation by LPS-OS along with augmented tumour necrosis factor-α, and interleukin-β levels. Maintenance of rats under hypoxic conditions for 15 days prior to the LPS-OS challenge effectively blunted the changes in this chain of effects. Moreover increases in antioxidative enzymes, such as Cu/ZnSOD, MnSOD and catalase, may further contribute to the beneficial effects of high altitude, as shown in the study reviewed.

Taken together, the findings of Yang et al. provide a detailed picture of how chronic hypoxia may precondition the kidney to better cope with LPS-OS. When considering that hypoxia also stimulates erythropoietin synthesis, more possible routes of renal preconditioning appear likely. Erythropoietin is well known as a potent mediator of preconditioning in the brain and heart (Dawson, 2002; Baker, 2005). Lately it has been suggested that erythropoietin is also involved in the preconditioning of the kidney (Sharples & Yaqoob, 2006).

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