Activation of the Renin-Angiotensin System and Chronic Hypoxia of the Kidney

175 Hypertens Res Vol.31 (2008) No.2 p.175-184 Review Activation of the Renin-Angiotensin System and Chronic Hypoxia of the Kidney Masaomi NANGAKU1) and Toshiro FUJITA1) 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) Key Words: ischemia, chronic kidney disease, angiotensin receptor blocker, oxidative stress Introduction While chronic kidney disease (CKD) was previously believed to be relatively uncommon, it is now recognized as a common public health problem of global concern (1). The most important adverse outcomes of CKD include not only the complications of decreased glomerular filtration rate (GFR) and progression to kidney failure, but also an increased risk of cardiovascular disease (2). Indeed, the strong association between CKD and cardiovascular disease has led the American Heart Association and National Kidney Foundation to recommend that all patients with cardiovascular disease be screened for evidence of kidney disease (3). Primary insults differ among kidney diseases, including glomerulonephritis, diabetic nephropathy, and hypertensive nephrosclerosis. However, once renal damage reaches a certain threshold, progression of renal disease is consistent, irreversible, and largely independent of the initial insult. Functional impairment of the kidney correlates better with the degree of tubulointerstitial damage than with that of glomerular injury, and it is widely recognized that the final common pathway which mediates the deterioration of kidney failure is to be found in the tubulointerstitium (4). From the 1)Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo, Japan. This work was supported in part by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (grant number 19390228). Address for Reprints: Masaomi Nangaku, M.D., Ph.D., Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, 7–3–1 Hongo, Bunkyo-ku, Tokyo 113–8655, Japan. E-mail: Received May 9, 2007; Accepted in revised form August 13, 2007. 176 Hypertens Res Vol. 31, No. 2 (2008) Fig. 1. The microvasculature of the nephron. The peritubular capillary plexus is fed by glomerular efferent arterioles and supplies oxygen to tubular and interstitial cells (modified from Nangaku (13)). Blockade of the Renin-Angiotensin System to Treat CKD While renal disease causes an increase in blood pressure (BP), high BP in turn accelerates the loss of function in the diseased kidney. The treatment of hypertension is thus now an important component in the treatment of CKD patients, not only to prevent cardiovascular complications but also to protect the kidney (5, 6). Meta-regression analyses have indicated that BP reduction accounts for 50% of the variance in GFR decline and that each 10-mmHg reduction in mean arterial pressure (down to 92 mmHg) confers a benefit in GFR preservation of 3.7–5.0 mL/min per year (7–10). On this basis, stricter control of BP is recommended in patients with kidney injury. Further, to maximize the protection of residual renal function, many clinical practice guidelines now suggest initial therapy with reagents to block the renin-angiotensin system (RAS). Why is blockade of RAS considered the gold standard in the treatment of patients with CKD? A large number of prospective, randomized, controlled studies have demonstrated the beneficial effects of angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs). These studies are covered in detail in our previous overview but, taken together, they ascribe the profound beneficial effects of blockade of RAS to reno-protection that goes beyond mere BP reduction (11). In particular, Weinberg et al. reported that the BP-lowering effects of an ARB, candesartan cilexetil (approved dosage range in Japan up to 12 mg/day), reached a plateau when doses were increased to 96 mg/day. In contrast, they observed dose-related reductions in urinary protein excretion without any further lowering of BP (12). While previous studies emphasized the amelioration of intraglomerular hypertension as a BP-independent reno-protective mechanism of blockade of RAS, more recent studies have clarified that the beneficial mechanism of ACEIs and ARBs includes a crucial role in ameliorating chronic hypoxia in the kidney. Microvasculature of the Kidney Although the kidneys receive a very high blood flow, oxygen extraction in the kidney is actually relatively low. This is due to its unique vasculature system, in which oxygen shunt diffusion occurs between arterial and venous vessels that run in close parallel contact in the kidney. Further, the maintenance of homeostasis mandates the reabsorption of a large fraction Nangaku et al: RAS and Kidney Hypoxia of the sodium and water filtered by the glomeruli. This reabsorption process is driven by active transport and uses a large amount of oxygen. As a consequence, the kidneys are particularly susceptible to hypoxic injury, and recent studies emphasize chronic hypoxia in the tubulointerstitium as a final common pathway to end-stage kidney disease (13–18). In the kidney, afferent arterioles arise from the interlobular arteries. Except for branches that go toward the pelvic mucosa, all blood from the interlobular and arc (...truncated)