Recent studies emphasize the role of chronic
hypoxia in the kidney as a final common pathway to
end-stage renal failure (
ESRD).
Hypoxia of tubular cells leads to apoptosis or epithelial-mesenchymal transdifferentiation, which in turn exacerbates the
fibrosis of the kidney with the loss of peritubular capillaries and subsequent chronic
hypoxia, setting in train a vicious cycle whose end-point is
ESRD. While fibrotic kidneys in an advanced stage of renal disease are devoid of peritubular capillary blood supply and oxygenation to the corresponding region, imbalances in vasoactive substances can cause chronic
hypoxia even in the early phase of
kidney disease. Among various vasoactive substances, local activation of the renin-angiotensin system (RAS) is particularly important because it can lead to the constriction of efferent arterioles, hypoperfusion of postglomerular peritubular capillaries, and subsequent
hypoxia of the tubulointerstitium in the downstream compartment. In addition,
angiotensin II induces oxidative stress via the activation of
NADPH oxidase. Oxidative stress damages endothelial cells directly, causing the loss of peritubular capillaries, and also results in relative
hypoxia due to inefficient cellular respiration. Thus,
angiotensin II induces renal
hypoxia via both hemodynamic and nonhemodynamic mechanisms. In the past two decades, considerable gains have been realized in retarding the progression of
chronic kidney disease by emphasizing blood pressure control and blockade of the RAS. Chronic
hypoxia in the kidney is an ideal therapeutic target, and the beneficial effects of blockade of RAS in
kidney disease are, at least in part, mediated by the amelioration of local
hypoxia. (Hypertens Res 2008; 31: 175-184).