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Cellular processes leading to renal tubular hypertrophy may contribute to the development of progressive renal disease. Angiotensin II (ANG II) is a prime agent that has been linked to the progression of renal disease by a host of mechanisms, including the induction of tubular epithelial hypertrophy and stimulation of extracellular matrix biosynthesis. All components of a functional renin-angiotensin system reside within the renal tubule. Epithelial cells exhibit distinct patterns of growth behavior after stimulation with ANG II (namely, hypertrophy of proximal tubule segments and proliferation of more distal segments). The hypertrophic action of ANG II is mediated through high-affinity AT1-receptors, involves activation of pertussis-toxin sensitive G1 proteins, and depends on a decrease in intracellular cAMP. In addition, ANG II induces sequential activation of MAP kinases and S6 kinase, and leads to activation of early immediate genes and the modulation of a series of cyclins and cyclin-dependent kinases. There is also compelling evidence that the ANG II-induced epithelial hypertrophy and the stimulated-synthesis of collagen type IV are mediated by increased transcription and production of TGF-beta. ANG II-mediated inhibition of protein degradation may further increase protein content. The hypertrophic response to ANG II is greater in medium with high glucose concentration. Blockade of the action of ANG II prevents the renal hypertrophy and the tubulointerstitial fibrosis in animal models of chronic renal diseases (independent of changes in systemic or glomerular hemodynamics), in part through interception of ANG II-mediated induction of TGF-beta expression.
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PMID:Renal tubular hypertrophy induced by angiotensin II. 931 13

The efficacy of angiotensin converting enzyme inhibitors (ACEI) in slowing the advancement of chronic renal disease attests to the importance of angiotensin II (Ang II) in the pathophysiological mechanisms underlying disease progression. It is apparent from studies of the effects of orally-active AT1 receptor antagonists (AT1RA) in experimental models of chronic progressive renal disease, that AT1RA have broadly similar effects to those of ACEI, implying that the favorable effects of ACEI on systemic and renal hemodynamics and indices of glomerular injury are mediated, in large part, by reducing the action of Ang II at AT1 receptors. The possibility remains, however, that differences in the modes of action of ACEI and AT1RA are significant in terms of renal protection and that the two classes of drugs are not therapeutically equivalent. Thus far, however, virtually all experimental studies comparing the renal protective effects of ACEI versus AT1RA have failed to show any convincing differences between the two classes of drug that cannot be attributed to discrepancies in the levels of blood pressure control achieved. As many rodent studies have adopted protocols originally designed to distinguish between the effects of treatment versus no treatment, however, it may be premature to conclude that ACEI and AT1RA are, essentially, therapeutically equivalent. Since both classes of drug have such potent renoprotective effects, the extent of injury that develops in treated rats may be so slight as to compromise the sensitivity of the experimental comparison. Fresh experimental approaches may be required to overcome this issue and resolve any outstanding questions concerning the therapeutic equivalence of AT1RA and ACEI in slowing the progression of renal disease.
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PMID:Angiotensin receptor antagonists in experimental models of chronic renal failure. 940 43

Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) in the United States, and accounts for 35% of all the patients with ESRD entering a dialysis program; 63% of patients with diabetic nephropathy have type II diabetes mellitus. Hypertension is a major risk factor for renal disease and is common in people with diabetes mellitus. Strategies for preventing the progression of renal failure in patients with diabetes mellitus include glycemic control, and control of blood pressure. Blocking the renin-angiotensin system (RAS) slows the progression of established diabetic nephropathy in type I diabetes mellitus, and inhibiting angiotensin II formation retards or impedes the progression from microalbuminuria to established diabetic nephropathy (macroproteinuria) in people with type I diabetes mellitus. The situation could be the same for people with type II diabetes mellitus. The ability of RAS blockade using irbesartan, an AT1 angiotensin II receptor antagonist, to slow the progression in renal failure has been compared with that of the calcium channel blocker amlodipine and placebo in a pilot study. The results suggest that blockade of the RAS, in this case with irbesartan, is at least equivalent to calcium channel blockers with respect to antihypertensive efficacy, but provides better renoprotective benefits.
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PMID:Renoprotection and renin-angiotensin system blockade in diabetes mellitus. 943 77

RENIN-ANGIOTENSIN ANTAGONISTS: The renal effects of angiotensin II receptor antagonists (AT1 blockers) can be compared with another class of drugs inhibiting the renin-angiotensin-aldosterone system, i.e. the angiotensin I converting enzyme inhibitors (ACE1). SIMILAR BUT SPECIFIC EFFECTS: The renal effects of these two classes of drugs are similar but each class has specific effects explained by several mechanisms. i) The system includes a large number of active peptides (angiotensin II, angiotensin III, angiotensin 1-7) which exert various effects according to their specific receptor(s): ii) several types of angiotensin II receptors have been identified (AT1, AT2, AT4 ...). Only AT1 blockers are available in clinical practice. iii) Receptor or enzyme blockade can produce varying effects; ACE inhibition is not specific since increased bradykinin activity is associated with the suppression of angiotensin peptide generation. EXPERIMENTAL AND CLINICAL TRIALS: Experimental and recent clinical studies have shown that AT1 blockers can induce, like ACE1, hypotension, renal vasodilation and natriuresis. The definite effects on discrete renal structures (vessels, glomeruli, tubules) differ however in magnitude which may suggest specific indications according to the pathophysiological background (renal disease, congestive heart failure, etc.).
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PMID:[Renal effects of AT1 angiotensin receptor antagonists (AT1ra)]. 953 2

ACE inhibitors have achieved widespread usage in the treatment of cardiovascular and renal disease. ACE inhibitors alter the balance between the vasoconstrictive, salt-retentive, and hypertrophic properties of angiotensin II (Ang II) and the vasodilatory and natriuretic properties of bradykinin and alter the metabolism of a number of other vasoactive substances. ACE inhibitors differ in the chemical structure of their active moieties, in potency, in bioavailability, in plasma half-life, in route of elimination, in their distribution and affinity for tissue-bound ACE, and in whether they are administered as prodrugs. Thus, the side effects of ACE inhibitors can be divided into those that are class specific and those that relate to specific agents. ACE inhibitors decrease systemic vascular resistance without increasing heart rate and promote natriuresis. They have proved effective in the treatment of hypertension, they decrease mortality in congestive heart failure and left ventricular dysfunction after myocardial infarction, and they delay the progression of diabetic nephropathy. Ongoing studies will elucidate the effect of ACE inhibitors on cardiovascular mortality in essential hypertension, the role of ACE inhibitors in patients without ventricular dysfunction after myocardial infarction, and the role of ACE inhibitors compared with newly available angiotensin AT1 receptor antagonists.
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PMID:Angiotensin-converting enzyme inhibitors. 957 53

Morbidity and mortality due to end-stage renal failure has become a major health concern in recent years and there is clear evidence that arterial hypertension constitutes a powerful risk factor for the progression of renal disease. Several studies have documented the benefit of blood pressure control on renal function, and it is increasingly recognized that antihypertensive therapy aimed at reducing blood pressure well below the target value of 140/90 mmHg further improves the overall renal survival rate. Different classes of antihypertensive agents show disparate specific nephroprotective properties that are unrelated to their blood pressure lowering properties. ACE inhibitors and calcium channel blockers have been reported to ameliorate renal function by favorably modifying renal and intraglomerular hemodynamics. In addition, both drugs exert beneficial effects on non-hemodynamic parameters of renal function. In contrast, beta-blockers and diuretics, although still being solely recommended as first line drugs in the management of arterial hypertension, can have adverse effects on renal function. Recently, long-term randomized controlled trials have consistently demonstrated the superior nephroprotective value of ACE inhibitors on renal function outcome. Whether AT1 receptor antagonists have similar effects on long-term renal survival is still under investigation. The outcome of forthcoming clinical trials is likely to influence clinical guidelines and optimize the medical regimen of human essential hypertension in patients with chronic renal insufficiency.
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PMID:Nephroprotection by antihypertensive therapy. 983 72

Arterial hypertension, which represents a common problem in patients with renal transplant, contributes to the cardiovascular morbidity and mortality of these patients. The most usual immunosuppressive drugs (cyclosporine and FK-506) collaborate on the development of hypertension. Calcium channel blockers are the most habitually used antihypertensive drugs in this population, although its long-term hemodimamycs effects could be deleterious especially in transplanted patients with chronic graft nephropathy. Losartan, a specific blocker of angiotensin II (AT1) receptors, has demonstrated a potent antihypertensive effect with a good safety and tolerance profile. The glomerular effects of losartan could be useful in transplanted patients. The present open, prospective and multicenter study evaluated the efficacy and safety of losartan in the treatment of hypertension in a group of patients with a renal transplant. Seventy-six patients with systolic blood pressure > or = 140 and/or diastolic blood pressure > or = 90 mm Hg, and/or patients on therapy with one antihypertensive drug and related side effects were included. After inclusion, therapy with losartan 50 mg/24 hr was started, discontinuing the previous antihypertensive therapy and/or therapy which caused the side effects. At four weeks, if blood pressure (BP) was not controlled, hydrochlorothiazide 25 mg or furosemide 40 mg/24 hr was added. At baseline and at weeks 2, 4, 8 and 12, the following parameters were monitored: BP, creatinine, hematocrit, hemoglobin, glucose, ions, uric acid, cholesterol, triglycerides, bilirubin, SGOT, SGPT, GGT, LDH, calcium, phosphate, alkaline phosphatase, proteinuria, and both cyclosporine and FK-506 levels in whole blood. Sixty-seven patients completed the 12-week study period. Mean blood pressure decreased from 113 +/- 10 to 102 +/- 9 mm Hg at the end of the study (P < 0.0001); 38 of the 67 patients (56.7%) who completed the study had a SBP lower than 140 mm Hg and a DBP lower than 90. These blood pressures were obtained in 30 patients on monotherapy with losartan (78.9%). Proteinuria decreased significantly at week 4 and was confirmed at week 12, especially in patients with proteinuria > or = 300 mg/24 hr. Nine patients were withdrawn during the study period for different reasons. Serum creatinine showed a slight, non-clinically significant increase at week 4, remaining stable until the end of the study. Two patients developed a mild normocytic anemia, and three others presented a mild impairment of pre-existent anemia. No interactions with cyclosporine or FK-506 were described. These results indicate that losartan is effective in reducing BP in hypertensive patients with a renal transplant. It has a good tolerance profile and does not interfere with immunosuppressive therapy.
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PMID:Efficacy and safety of losartan in the treatment of hypertension in renal transplant recipients. 983 98

Cellular and molecular events contributing to tubulointerstitial fibrosis of the kidney during obstructive nephropathy are driven in large part through increased angiotensin II levels in the obstructed kidney. Angiotensin converting enzyme inhibition or AT1 receptor antagonism have been shown to ameliorate the fibrosis of the kidney due to obstruction of the ureter. In this investigation, we determine the effects of the AT2 receptor antagonist PD-123319 on pathophysiological events within the kidneys of rats with unilateral ureteral obstruction. Treatment with PD-123319 was found to exacerbate the increase in interstitial volume and collagen IV matrix score of the ureteral obstructed kidney. Monocyte/macrophage infiltration of the injured kidney was no different between treated and untreated animals. The AT2 receptor antagonist did, however, inhibit apoptosis of tubular cells, alpha-smooth muscle actin expression within the interstitium, and p53 expression in the ureteral obstructed kidney. These results suggest that angiotensin II operating through the AT2 receptor exerts an antifibrotic effect on the kidney during obstructive nephropathy in opposition to the profibrotic effects of angiotensin II operating through the AT1 receptor.
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PMID:Effect of AT2 receptor blockade on the pathogenesis of renal fibrosis. 988 78

At the present time we cannot assume that the proven benefits of ACEI on renal disease will be reproduced by using AT1-ra. With potentially differing modes of activity of these drugs, they cannot be seen as interchangeable and ACEI should remain the drug of choice in patients with progressive renal disease unless they are not tolerated. It is possible that AT1-ra may offer additional advantages in some patients or that synergy exists between the two agents, but this view will remain entirely speculative unless proper trials are conducted. Despite the results of the ELITE study [22], the uncertainty regarding the use AT1-ra in cardiovascular disease mirrors that of renal disease. This issue is obviously of relevance to the nephrologist in view of the spectrum of cardiac disease that accompanies chronic renal failure, such as left ventricular hypertrophy and cardiac failure, which provide multiple indications for manipulation of RAS. Despite their renoprotective effect, previous studies on ACEI [3,4] have not shown an overall reduction in mortality and this issue needs to be addressed in addition to renoprotection in studies comparing AT1-ra and ACEI.
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PMID:Angiotensin converting enzyme inhibitors and angiotensin receptor (AT1) antagonists: either or both for primary renal disease? 1005 68

Pharmacologic interruption of the renin-angiotensin system (RAS) with angiotensin-converting enzyme inhibitors (ACEI) is considered a standard therapeutic intervention for patients with chronic renal disease, regardless of whether systemic hypertension is present. The advent of orally active angiotensin receptor blockers (ARB) increases the number of therapeutic options for inhibiting the RAS in patients with chronic renal diseases. Clinical studies of ARB that can be compared with large-scale ACEI clinical trials have yet to be completed. More than a dozen experimental studies comparing ARB with ACEI suggest that the two classes of drugs share similar renoprotective properties. Like ACEI, ARB are effective antihypertensive and antiproteinuric agents, which greatly reduce glomerular and tubulointerstitial scarring. Although both reduce stimulation of the AT1 receptor, ARB lack the kinin-potentiating effects of ACEI. ARB may exert antifibrotic actions via the AT2 receptor, through increased levels of angiotensin II resulting from AT1 receptor blockade. Despite these pharmacologic distinctions, recent studies have not detected differences in renoprotection between ARB and ACEI. In the context of RAS inhibition, the magnitude of antihypertensive and antiproteinuric effects achieved appears to be the major determinant of renoprotection, not the class of drug used. Thus, experimental data suggest that ARB will fulfill their promise as effective agents to be used as mainstays in multifaceted clinical strategies designed to slow or arrest the progression of chronic renal disease. Confirmation of this view awaits the results of clinical trials.
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PMID:Angiotensin receptor blockers in chronic renal disease: the promise of a bright clinical future. 1020 84


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