Angiotensin-induced hypoxia in the kidney: Functional and structural changes of the renal circulation

Recent studies emphasize the role of chronic hypoxia in the kidney as a final common pathway to end-stage renal disease (ESRD). Hypoxia of tubular cells leads to apoptosis or epithelial-mesenchymal transdifferentiation. This in turn exacerbates fibrosis of the kidney with loss of peritubular capillaries and subsequent chronic hypoxia, setting in train a vicious cycle whose end point is ESRD. To support this notion, our studies utilizing various techniques such as hypoxia-sensing transgenic rats revealed hypoxia of the kidney in various disease models. While fibrotic kidneys with advanced renal disease are devoid of peritubular capillary blood supply and oxygenation to the corresponding region, imbalances in vasoactive substances and associated intrarenal vasoconstriction can cause chronic hypoxia even at the early phase of kidney disease. Among various vasoactive substances, local activation of RAS is especially important because it can lead to constriction of efferent arterioles, hypoperfusion of postglomerular peritubular capillaries, and subsequent hypoxia of the tubulointerstitium in the downstream compartment. Recent studies using BOLD-MRI showed an immediate decrease of oxygen tension in the kidney after angiotensin II infusion. In addition, angiotensin II induces oxidative stress via activation of NADPH oxidase. Oxidative stress damages endothelial cells directly, causing the loss of peritubular capillaries. Oxidative stress also results in relative hypoxia due to inefficient cellular respiration. Thus, angiotensin II induces renal hypoxia via both hemodynamic and nonhemodynamic mechanisms. While the beneficial effects of blockade of RAS in kidney disease are, at least in part, mediated by amelioration of hypoxia, recent studies have also elucidated the mechanism of hypoxia-induced gene regulation via the HIF-HRE system. This has given hope for the development of novel therapeutic approaches against hypoxia in the kidney.