Hyperbaric oxygen treatment augments the efficacy of cilazapril and simvastatin regimens in an experimental nephrotic syndrome model

Oxidative stress is related to endothelial dysfunction (ED) and cardiovascular outcomes in patients with chronic kidney disease. Increased asymmetric dimethylarginine (ADMA) levels are among the main causes of ED. We aim to investigate any association between ED and ADMA levels, as well as levels of oxidative stress markers, in patients with chronic kidney disease. One hundred fifty-nine patients without diabetes with chronic kidney disease were studied. Staging was performed according to glomerular filtration rate, determined as stages 1 to 5 according to the Kidney Disease Outcomes Quality Initiative (n = 30, 33, 28, 32, and 36, respectively). The control group consisted of 30 healthy subjects. Oxidative stress markers (plasma malondialdehyde [MDA], erythrocyte superoxide dismutase [SOD], glutathione peroxidase [GSH-Px]), trace elements (erythrocyte zinc [EZn], erythrocyte copper [ECu]), plasma selenium (Se), and serum ADMA were studied. Brachial artery endothelium-dependent vasodilatation (FMD) was calculated for all. FMD, SOD, GSH-Px, EZn, ECu, and Se values were lower, whereas MDA and ADMA levels were higher in patients than controls. Glomerular filtration rate correlated negatively with MDA and ADMA levels and positively with FMD, SOD, and GSH-Px values. These parameters were significantly different among patients with stages 2, 3, 4, and 5 (hemodialysis group; P < 0.001 for all). Regression analysis showed that ADMA (beta = -0.228; P < 0.01), SOD (beta = 0.405; P < 0.001), and oxidized low-density lipoprotein levels (beta = -0.428; P < 0.001) were related independently to FMD, whereas glomerular filtration rate was not involved in the model. The present results imply that FMD, oxidative stress, and ADMA levels all are associated with stage of chronic kidney disease. Additionally, levels of oxidative stress markers and ADMA independently determine endothelial function.

The kidney shows a remarkable discrepancy between blood supply and oxygenation. Despite high blood flow and oxygen delivery, oxygen tensions in the kidney are comparatively low, in particular in the renal medulla. The reason for this lies in the parallel arrangement of arterial and venous preglomerular and postglomerular vessels, which allows oxygen to pass from arterioles into the postcapillary venous system via shunt diffusion. The limitation in renal tissue oxygen supply renders the kidney susceptible to hypoxia and has long been recognized as an important factor in the pathogenesis of acute renal injury. In recent years, evidence has accumulated that hypoxia does also play a significant role in the pathogenesis and progression of chronic renal disease, because different types of kidney disease are usually associated with a rarefication of postglomerular capillaries. In both acute and chronic diseases, tissue hypoxia does not only imply the risk of energy deprivation but also induces regulatory mechanisms and has a profound influence on gene expression. In particular, the transcription factor hypoxia inducible factor (HIF) is involved in cellular regulation of angiogenesis, vasotone, glucose metabolism, and cell death and survival decisions. HIF has been shown to be activated in renal disease and presumably plays a major role in protective responses to oxygen deprivation. Recent insights into the regulation of HIF increase our understanding of the role of hypoxia in disease progression and open new options to improve hypoxia tolerance and to induce nephroprotection.