How Does Angiotensin II Cause Renal Injury?

ased on several important clinical trials, the Seventh Report of the Joint National Committee on Preven- tion, Detection, Evaluation, and Treatment of High Blood Pressure 7 (JNC 7) approves the use of angiotensin- converting enzyme (ACE) inhibitors and/or angiotensin re- ceptor blockers (ARBs) in the first-line treatment for hyper- tension in subjects with chronic renal insufficiency, in diabetic subjects with proteinuria, and in black subjects with renal insufficiency and proteinuria, because these agents appear to provide renoprotection in these conditions. 1 The observation that agents that interfere with the renin-angioten- sin system (RAS) might be useful in subjects with renal insufficiency seems at first to be counterintuitive, because many subjects with chronic renal insufficiency are volume- expanded, which acts to inhibit the RAS. However, in renal insufficiency, other mechanisms that stimulate renin may be involved, including intrarenal microvascular disease causing ischemia, hyperuricemia, and low 1,25-dihydroxyvitamin D levels. Renal injury will also activate renal afferent nerves to stimulate -adrenergic output from the central nervous sys- tem that can stimulate renin release. Activation of the local RAS has also been shown in renal injury, indicated by upregulation of ACE and the infiltration of leukocytes ex- pressing angiotensin II. 2 A variety of mechanisms has been suggested by which angiotensin II causes renal injury. Angiotensin II may cause pressure-induced renal injury via its ability to induce sys- temic and glomerular hypertension or cause ischemia- induced renal injury secondary to intrarenal vasoconstriction and decreased renal blood flow. Angiotensin may also cause tubular injury secondary to angiotensin-induced proteinuria. Angiotensin II also activates renal fibroblasts to become myofibroblasts, stimulates the production of the profibrotic cytokine TGF-, induces oxidative stress, stimulates chemo- kines and osteopontin that may cause local inflammation, and stimulates vascular and mesangial cell proliferation and hypertrophy. Taken together, these data provide an excellent rationale for blocking the RAS in subjects with renal disease, because angiotensin II has hemodynamic and nonhemody- namic mechanisms by which it can cause renal damage. Nevertheless, the mechanism by which blocking the RAS is protective remains controversial. Substantial data, primar- ily in studies of diabetic subjects and/or subjects with renal insufficiency, suggest that blocking the RAS slows renal injury via blood pressure (BP)-dependent and BP- independent pathways.3,4 In contrast, studies in several ex- perimental models of renal disease suggest that the greater protection of ACE inhibitors is caused by better continuous BP control, which is not evident by single daily BP measure- ments.5- 8 In the remnant kidney model of progressive renal disease, for example, renoprotection correlates directly with continuous 24-hour systolic BP measurements, regardless of whether agents that block the RAS are used.6 Several clinical studies, including the recent ALLHAT trial, are consistent with a critical, if not major, role for strict BP control in slowing renal disease.9 To better understand what component of renal injury is caused by the hypertensive effects of angiotensin II, we previously examined the histologic changes occurring in the kidneys of the 1-clip 2-kidney model of hypertension.10 In