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Recent studies have shown that proteoglycans play an important role in the development of vascular disease and renal failure. In this study, the effects of angiotensin II (AngII) type 1 (AT1) and type 2 (AT2) receptor stimulation on glycosaminoglycan and proteoglycan core protein synthesis in vascular smooth muscle cells (VSMC) were examined. Treatment of AT1 receptor-expressing VSMC with AngII resulted in a dose-dependent and time-dependent increase (2- to 4-fold) in (3)H-glucosamine/(35)S-sulfate incorporation, which was abolished by pretreatment with the AT1 receptor antagonist, losartan. The effects of AngII were inhibited by the epidermal growth factor receptor inhibitor, AG1478, and the mitagen-activated protein kinase kinase inhibitor, PD98059, but not the protein kinase C inhibitors, chelerythrine and staurosporine. AngII treatment also resulted in significant increases in the mRNA of the core proteins, versican, biglycan, and perlecan. The effects of AT2 receptor stimulation were examined by retroviral transfection of VSMC with the AT2 receptor. Stimulation of the AT2 receptor in these VSMC-AT2 cells resulted in a significant (1.3-fold) increase in proteoglycan synthesis, which was abolished by the AT2 receptor antagonist, PD123319, and attenuated by pretreatment with pertussis toxin. These results implicate both AT1 and AT2 receptors in the regulation of proteoglycan synthesis and suggest the involvement of epidermal growth factor receptor-dependent tyrosine kinase pathways and G alpha i/o-mediated mechanisms in the effects of the two receptors.
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PMID:Regulation of vascular proteoglycan synthesis by angiotensin II type 1 and type 2 receptors. 1172 29

The effect on renal function and efficacy of the angiotensin II AT1-receptor blocker (ARB), telmisartan, were compared with those of the angiotensin-converting enzyme inhibitor, enalapril, for the treatment of mild-to-moderate hypertension (diastolic blood pressure [DBP] 95-114 mmHg) in the presence of moderate renal failure (creatinine clearance [Ccr] 30-80 ml/minute). The study was multicentre, double-blind, double-dummy and active-controlled in design, with patients randomised in a 2:1 ratio to receive telmisartanor enalapril. After a two-week placebo run-in period, the 71 eligible patients received either telmisartan, 40 mg, orenalapril, 10 mg, once-daily for four weeks. Thereafter, doses were titrated to telmisartan 80 mg or enalapril 20 mg once-daily if supine trough DBP was still > or =90 mmHg. After a further four weeks, dose titration was again performed, as required, to telmisartan, 80 mg,or enalapril, 20 mg, or frusemide was given in addition if the double dose was already being administered. Mean Ccr decreases of 4.6% for telmisartan and 2.8% forenalapril were not clinically significant. Adverse events occurred in 12 (26.7%) telmisartan-treated patients and in 12 (46.2%) patients receiving enalapril. The mean reduction in supine trough DBP from baseline to the last available value was 12.5 mmHg for telmisartan,compared with 11.9 mmHg for enalapril. A full (reduction of >or=10 mmHg) or partial (reduction of 7-9 mmHg) response occurred in 78% of telmisartanpatients and 65% of enalapril patients. In the enalapril group, 43% of patients required frusemide, compared with 29% of those in the telmisartan group. In conclusion, telmisartan lacks detrimental effect on renal function, is effective in the treatment of mild-to-moderate hypertension in patients with moderate renal failure,and is comparable to enalapril.
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PMID:Evaluation of the safety and efficacy of telmisartan and enalapril, with the potential addition of frusemide, in moderate-renal failure patients with mild-to-moderate hypertension. 1188 Nov 31

The renal community is faced with an ever increasing number of patients reaching end-stage renal failure. Clinical studies have provided clear evidence that angiotensin-converting enzyme (ACE) inhibitors, and probably also AT1 receptor antagonists, at least in patients suffering from type 2 diabetes, slow disease progression to end-stage renal failure. This protective effect of drugs interfering with the renin-angiotensin system (RAS) are in part independent of reduction in systemic blood pressure, but involve normalization of glomerular hyperperfusion and hyperfiltration, restoration of altered glomerular barrier function, and reduction of stimulated tubular fluid reabsorption. Angiotensin II (ANG II) has emerged in the last decade as a multifunctional cytokine exhibiting many non-hemodynamic properties such as acting as a growth factor and profibrogenic cytokine, and even having proinflammatory properties. This review tries to bridge the classical hemodynamic actions of ANG II in the kidney with the more recently characterized effects of this vasopeptide. Finally, clinical implications are suggested based on data from clinical studies. A thorough understanding of the RAS is important to recognize the potential of nephroprotective strategies through inhibition of its components.
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PMID:The renin-angiotensin system and progression of renal disease: from hemodynamics to cell biology. 1241 25

Human immunoglobulin A is represented by two structurally and functionally distinct subclasses: IgA1 and IgA2. IgA1, which is almost exclusively present in the mesangial deposits in IgA nephropathy patients, contains in its hinge region three to five O-lined carbohydrate chains. A fraction of IgA1 molecules in the circulation of IgA nephropathy patients exhibits aberrant glycosylation. As a result of changes in glycosylation, the neoepitopes represented by glycans are exposed and recognized by naturally occurring antibodies with antiglycan specifciities, and immune complexes are generated. The deposits of these immune complexes in the glomerular mesangia elicit inflammatory response known as IgA nephropathy. Epidemiological studies have shown that dominant hematuria, either isolated or combined with mild proteinuria, is the most frequent urinary syndrome in glomerulonephritis. The morphologic finding of this syndrome is most frequently IgA nephropathy. Originally considered a benign disease, IgA nephropathy is now recognized as a frequent cause of chronic renal failure. The progression is signalized by increasing proteinuria and hypertension. Therefore, a control of blood pressure and lowering of proteinuria remain the corner-stones of the treatment. Angiotensin converting enzyme inhibitors and AT1 blockers may lower both blood pressure and proteinuria and are now increasingly promoted even for treatment of normotensive patients. Steroids are administered to patients with severe proteinuria. High-doses of fish oil seem to slow down the rate of renal failure.
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PMID:[IgA nephropathy. Significance of immunoglobulin A glycosylation in pathogenesis and clinical presentation]. 1265 29

In Germany, 36% of all new chronic dialysis patients have diabetic nephropathy. The majority are type 2 diabetics. Early intervention has the greatest effect. Incipient nephropathy can be diagnosed by evidence of microalbuminuria (30-300 mg albumin/g creatinine). Proteinuria on the standard test strip (>300 mg/g) indicates manifest nephropathy followed by progressive renal failure. Important cofactors for progression are hypertension, hyperglycemia, and smoking. Low normal blood pressure levels (<130/80 mmHg without and <125/75 mmHG with proteinuria) based on ACE inhibitors/AT1 blockers are the goal. Combination therapies are frequently necessary. This can often reverse microalbuminuria. Chronic renal failure requires special attention (e.g. bone metabolism, anemia, acidosis). Timely initiation of renal replacement therapy (GFR <15 ml/min) reduces morbidity and mortality. In addition to hemo- and peritoneal dialysis, early kidney and in individual cases of type 1 diabetes combined kidney/pancreas transplantation is appropriate.
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PMID:[Diagnostics and therapy of diabetic nephrology]. 1273 10

Irbesartan is a long-acting angiotensin II antagonist acting specifically at the level of the Type 1-receptor subtype (AT1-receptor). This compound lowers blood pressure dose-dependently in hypertensive patients and has a placebo-like tolerability. The antihypertensive efficacy of irbesartan is greatly enhanced by the coadministration of a diuretic, and fixed-dose combinations of irbesartan and hydrochlorothiazide are now available. Irbesartan-based treatment appears especially effective for high-risk patients, such as those with diabetes, renal disease and cardiac hypertrophy. In patients with Type 2 diabetes, irbesartan delays the development of nephropathy as well as the progression of renal failure. Irbesartan may have antiatherosclerotic properties beyond those expected from blood pressure lowering per se: this AT1-blocker decreases the vascular oxidative stress and prevents the procoagulant as well as the pro-inflammatory effects of angiotensin II. Irbesartan given alone or in combination with a diuretic therefore represents a rational approach to treat hypertensive patients.
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PMID:AT1-receptor antagonism in hypertension: what has been learned with irbesartan? 1503 Feb 94

Conservative treatment implies procedures which involve normalization or improvement of metabolic disorders in chronic renal insufficiency and failure by medicamentous and dietary means. Keto amino acids administration can remarkable influence protein synthesis, metabolic acidosis, Ca-P and PTH levels, carbohydrate and lipid disorders, but has no effect on hyperfiltration. Long-term co-administration of rHuEPO and keto amino acids in CRF patients on LPD has accelerated metabolic effect associated with a delay in progression of renal failure and reduction of proteinuria. Also, concomitant administration of ACE inhibitors and angiotensin II AT1 receptor antagonist in CRF patients on LPD with KA was associated with significant decrease of proteinuria, amino-aciduria and, via its glomerulo-tubular action, it had also an effect on progression of CRF.
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PMID:[Present opinions on use of ketoanalog essential aminoacids in a conservative treatment of chronic renal insufficiency]. 1532 64

The results issued from experimental models and randomized controlled clinical trials have shown that the more intense is the blockade of the renin-angiotensin system (RAS), the more effective is the prevention of target organ damage. Combined inhibition of the RAS is aimed at more complete blockade of the system through action at two different sites, angiotensin I converting enzyme (ACE) and AT1 receptors. This is achieved either by neutralizing the rise in renin and angiotensin (Ang) I, which follows the interruption of the Ang II-renin negative feed-back loop, or by directly antagonizing Ang II, whose synthesis is in part independent of the RAS. By comparison with higher doses of single site RAS blockers, a combination of an ACE inhibitor and an AT1 receptor antagonist block more effectively the RAS. After the demonstration of its synergistic or additive blood pressure lowering effects in sodium depleted normotensive subjects and animal models, combined blockade of the RAS was shown to be more efficient than single site RAS blockade: 1. in lowering blood pressure in hypertensive patients; 2. in lowering proteinuria and possibly retarding progression of renal failure in patients with diabetic and non-diabetic nephropathy; 3. finally, in improving left ventricular remodelling, cardiac function status and cardiovascular morbidity and mortality in patients with congestive heart failure. The advantage offered by combining two RAS blockers is to increase the beneficial effect of cardioprotection and nephroprotection which are currently demonstrated with the highest doses of an ACE inhibitor or an AT1 receptor antagonist.
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PMID:[Blockade of the renin-angiotensin system by a combination of ACE inhibitors and AT1 receptor antagonists]. 1549 22

In patients with chronic renal failure, cancer incidence is increased. This may be related to an elevated level of genomic damage, which has been demonstrated by micronuclei formation as well as by comet assay analysis. Advanced glycation end products (AGEs) are markedly elevated in renal failure. In the comet assay, the model AGEs methylglyoxal- and carboxy(methyl)lysine-modified bovine serum albumin (BSA) induced significant DNA damage in colon, kidney, and liver cells. The addition of antioxidants prevented AGE-induced DNA damage, suggesting enhanced formation of reactive oxygen species (ROS). The coincubation with dimethylfumarate (DMF), an inhibitor of NF-kappaB translocation, reduced the genotoxic effect, thereby underscoring the key role of NF-kappaB in this process. One of the genes induced by NF-kappaB is angiotensinogen. The ensuing proteolytic activity yields angiotensin II, which evokes oxidative stress as well as proinflammatory responses. A modulator of the renin-angiotensin system (RAS), the angiotensin II (Ang II) receptor 1 antagonist, candesartan, yielded a reduction of the AGE-induced DNA damage, connecting the two signal pathways, RAS and AGE signaling. We were able to identify important participants in AGE-induced DNA damage: ROS, NF-kappaB, and Ang II, as well as modulators to prevent this DNA damage: antioxidants, DMF, and AT1 antagonists.
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PMID:Genotoxicity of advanced glycation end products: involvement of oxidative stress and of angiotensin II type 1 receptors. 1603 94

In the management of hypertension, the constant lowering of target pressures ever more frequently requires combination treatment in order to achieve the goals set. A combination of amlodipine and perindopril effectively lowered the blood pressure, and significantly reduced overall mortality, cardiovascular mortality, cardiovascular events and stroke risk in comparison with atenolol/bendroflumethiazide. In combination with both ACE inhibitors and AT1 blockers, diuretics reduced blood pressure more effectively that the respective components used alone. Now, however, the long-term use of diuretics is suspected of increasing the risk of terminal kidney failure and diabetes. This also means an enhanced probability of a cardiovascular event. In the ASCOT study, the combination of beta blocker and diuretic proved inferior to treatment with a calcium antagonist and ACE inhibitor. For the long-term application of diuretics as antihypertensive monotherapy, therefore, further comparative studies involving the latest antihypertensives are mandatory.
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PMID:[New tendencies in combination antihypertensive therapy]. 1635 34


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