UMLS:C0033687 - FACTA Search

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Query: UMLS:C0033687 (proteinuria)
24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is now abundant evidence that treatment with angiotensin-converting enzyme inhibitors (ACE-I) ameliorates the progression of chronic renal disease. Attention has therefore focused on the role of the renin angiotensin-aldosterone (RAA) system in mediating the development of progressive glomerulosclerosis and angiotensin II (Ang II) has been implicated in several processes thought to be important in the pathogenesis of this entity. Conversely, ACE is also known to catalyse the breakdown of bradykinin. Thus, ACE-I treatment results in elevated bradykinin levels which may cause selective efferent arteriolar dilatation, suggesting an alternative explanation for the beneficial effects of this class of drugs in chronic renal disease. The development of specific angiotensin type 1 receptor antagonists (AT1RA) has provided a means of testing the relative importance of these two mechanisms. In addition, AT1RAs differ from ACE-I in their effect on the RAA system in other aspects which may represent therapeutic advantages. This paper reviews studies which have compared ACE-I and AT1RAs in several rat models of chronic renal disease. Most have found similar beneficial effects including amelioration of proteinuria and glomerulosclerosis, which suggests that the effects of ACE-I are due to a reduction in Ang II activity and not due to increased levels of bradykinin. One long-term study has suggested greater renal protection with candesartan than with enalapril. However, conclusions as regards the relative efficacy of these two groups of agents in ameliorating the progression of chronic renal disease await the results of further long-term studies.
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PMID:ACE-I vs angiotensin II receptor antagonists: prevention of renal injury in chronic rat models. 1007 21

We hypothesized that short-term exposure to angiotensin II (Ang II) could result in structural and functional changes in the kidney that would favor sodium retention and the development of sustained hypertension. To test this hypothesis, rats were exposed to pressor doses (435 ng. kg-1. min-1) of Ang II for 2 weeks. The infusion of Ang II was associated with acute hypertension, renal dysfunction, proteinuria, and focal tubulointerstitial and vascular damage. At sites of the tubulointerstitial damage, there was a reduction in peritubular capillary endothelial cell staining. By use of immunostaining, we found focal loss of endothelial nitric oxide synthase (eNOS) in the peritubular capillaries at sites of injury and a generalized reduction in eNOS in collecting ducts, thin loops of Henle, and vascular bundles in the medulla. When the Ang II infusion ended, the rats became normotensive and renal function returned toward normal. However, exposure of the rats to high salt diet (4% NaCl) resulted in the redevelopment of hypertension after 3 to 4 weeks. Rats maintained on a high salt diet with no prior exposure to Ang II and rats placed on low salt diet (0.1% NaCl) after exposure to Ang II remained normotensive. Thus, we report a new model of salt-sensitive hypertension induced by transient exposure to pressor doses of Ang II. The mechanism may relate to microvascular injury with peritubular capillary loss coupled with functional changes, such as a loss in intrarenal nitric oxide formation, that could alter the ability of the kidney to excrete a salt load.
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PMID:Salt-sensitive hypertension develops after short-term exposure to Angiotensin II. 1020 40

It has been well demonstrated that angiotensin-converting enzyme inhibitors (ACEIs) can retard the progression of renal failure and kidney sclerosis in patients and animal models with glomerular diseases. The aim of this study was to observe the influences of ACEI on intrarenal Ang II and TGFbeta1 local formation and their relation to renal protective effects. Experimental glomerulosclerosis with nephrotic syndrome was induced in unilateral nephrectomized rats with repeated injections of adriamycin. Rats were randomly divided into three groups: 1) a sham-operated control group (n=8); 2) an NS group treated with ACEI (benazepril 4 mg/kg/d) (n=10), and 3) an NS group not treated (n=10). After 8 wk, serum, urine and renal tissue were collected for study. ACE activity and Ang II concentration in renal tissue were measured by colorimetry and radioimmunoassay, respectively. Immunohistochemistry staining was employed for transforming growth factor-beta1 (TGFbeta1) and extracellular matrix (ECM) examination. TGFbeta1 mRNA was assessed by in situ hybridization. Compared with those of non-treated nephropathy rats, ACE activity (13.39+/-5.02 vs. 49.13+/-12.92 U/ml, p< 0.01) and Ang II (402.61+/-80.22 vs. 751.63+/-137.45 pg/mg/pr p < 0.01) in renal tissue were significantly inhibited in the rats treated with ACEI. At the same time, proteinuria was significantly reduced (155.06+/-103.56 vs. 421.11+/-148.45 mg/24 h, p < 0.01) and renal function improved (Scr 76.3+/-33.1 vs. 107.1+/-71.0, p < 0.05), concomitant with a reduction in the glomerular sclerosis index (30.6+/-19.5 vs. 120.3+/-61.9, p < 0.01) and a reduction in ECM accumulation such as Col IV, III, LN and FN (29.2+/-9.8 vs. 76.8+/-12.4; 29.5+/-12.4 vs. 85.9+/-11.5; 26.0+/-5.1 vs. 69.6+/-1.73; 32.4+/-12.4 vs. 70.5+/-13.5; p< 0.01 in all cases). In the ACEI treated group, these histologic benefits coincided with a reduced expression of TGFbeta1 in both tubular cells and sclerosed glomeruli in protein as well as mRNA level. These findings provide further evidence that ACEI (benazepril) can prevent the progression of renal damage in both the function and morphologic changes which associated with a down-regulation of intrarenal Ang II level through the relative inhibition of renal ACE activity. The blocking of the intrarenal renin angiotensin system (RAS) might contribute to the inhibition of TGFbeta1 local formation and the TGFbeta1-mediated ECM accumulation that are related to the renal protective effects of ACEI.
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PMID:Renal protective effects of blocking the intrarenal renin-angiotensin system. 1051 46

In this study, we investigated the regulation and physiological role of heme oxygenase-1 (HO-1) in the kidney of rats with hypertension. Rats were continuously administered either angiotensin II (Ang II) or norepinephrine with an osmotic minipump for up to 7 days. Ang II infusion decreased the glomerular filtration rate (GFR) as determined through creatinine clearance (3.2+/-0.2 versus 1.2+/-0.2 mL/min with Ang II infusion, P<0.01) and increased proteinuria (9. 7+/-1.3 versus 28.1+/-7.2 mg/d with Ang II infusion, P<0.01). In contrast, norepinephrine did not alter these laboratory values. Ang II infusion significantly increased HO-1 expression in mRNA (442+/-98% of control at day 5, P<0.01) and protein levels (314+/-49% of control at day 5, P<0.01). Immunohistochemistry showed that in the kidney of normotensive rats, HO-1 was expressed mainly in the basal side in the renal tubules. After Ang II infusion, HO-1 staining was more extensively dispersed in the tubular epithelial cells. The intraperitoneal administration of zinc protoporphyrin, an HO inhibitor, to Ang II-infused rats further decreased GFR (0.8+/-0. 1 mL/min) and increased proteinuria (52.5+/-13.0 mg/d). In contrast, the administration of hemin, an HO inducer, ameliorated the Ang II-induced decrease in GFR (2.4+/-0.2 mL/min) and increase in proteinuria (9.3+/-4.5 mg/d). These data suggest that HO-1 upregulation in the kidney of Ang II-induced hypertensive rats may exert a renoprotective effect against Ang II-induced renal injury.
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PMID:Heme oxygenase-1 is upregulated in the kidney of angiotensin II-induced hypertensive rats : possible role in renoprotection. 1072 May 98

In landmark clinical trials, pharmacological inhibition of the renin-angiotensin system (RAS) with angiotensin-converting enzyme inhibitors (ACEIs) attenuated the decline in renal function associated with chronic renal disease (CRD). Hemodynamic and nonhemodynamic effects of angiotensin II (Ang II) attest to its central role in the pathogenesis of CRD. Angiotensin II subtype 1 receptor antagonists (AT1RA) differ from ACEI in their effects on the RAS and on bradykinin metabolism. Elevations in bradykinin levels associated with ACEI and stimulation of angiotensin subtype 2 receptors resulting from AT1RA may produce therapeutic effects unique to each class of drug. Nevertheless, in animal models of CRD, ACEI and AT1RA exert equivalent renoprotection, implying that their renoprotective effects result primarily from inhibition of Ang II-mediated stimulation of angiotensin subtype 1 receptors. Clinical data comparing ACEI and AT1RA therapy in renal disease are limited to short-term studies, which indicate that AT1RAs have equivalent effects to ACEI on the major determinants of CRD progression, namely blood pressure and proteinuria. AT1RAs were well tolerated, with side-effect profiles similar to placebo. Taken together, available evidence suggests that AT1RAs will share the renoprotective properties of ACEI in human CRD. Nevertheless, the results of long-term clinical trials are required before AT1RA can be recommended as an alternative to ACEI in renoprotective therapy.
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PMID:Renoprotective benefits of RAS inhibition: from ACEI to angiotensin II antagonists. 1079

The renin-angiotensin system (RAS) regulates blood pressure, volume, and electrolyte balance. Derangements of the RAS may contribute to hypertension and renal injury, particularly in patients with types 1 or 2 diabetes. Angiotensin-converting enzyme (ACE) inhibitors have been proven to be beneficial in patients with hypertension and diabetes by preventing or delaying the development and progression of proteinuria and glomerulosclerosis. Comparisons with other drug classes demonstrate renoprotective effects for ACE inhibitors that are independent of-and additive to-their systemic antihypertensive actions. These renal effects may derive from their preferential dilation of renal efferent arterioles, which further reduces intraglomerular pressure. Inhibition of angiotensin II (Ang II) synthesis is subtotal, however, because local non-ACE enzymes also convert Ang I to Ang II. The existence of alternative pathways for Ang II generation that are unaffected by ACE inhibitors raises questions about whether ACE is the optimal target for RAS suppression. Ang II receptor blockers (ARBs), which interrupt the RAS at the target-organ receptor level, will block the effect of angiotensin whether its production involved ACE or a non-ACE pathway. ARBs are currently undergoing clinical trials to assess their efficacy in hypertensive patients with nephropathy.
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PMID:Impact of angiotensin II on the kidney: does an angiotensin II receptor blocker make sense? 1098 55

A considerable amount of data have implicated angiotensin receptors (AT receptors) in the development and maintenance of essential hypertension and renovascular hypertension as well as in progressive renal pathologies. Inhibition of angiotensin II (Ang II) action by blocking Ang II formation through angiotensin-converting enzyme (ACE) inhibitors, or by blocking AT1 receptors directly using subtype-selective nonpeptide antagonists, has been found to attenuate the proteinuria, microalbuminuria, glomerulosclerosis, and nephrosclerosis in a variety of experimental models and in clinical trials. This review will first broadly discuss AT receptor subtypes in terms of their structure, function, tissue distribution and signaling. Secondly, the mechanistic differences between ACE inhibition and AT1 receptor blockade will be examined because these pharmaceutical agents are widely used tools to investigate the role of AT receptors in renal disease. Lastly, experimental models of essential hypertension, renovascular hypertension and progressive renal disease will be presented, which include the Fawn-hooded rat, the stroke prone spontaneously hypertensive rat, renal mass ablation and the 2K1C and 1K1C animal models. The overall goal of this review is to critically evaluate the data regarding the role of AT receptors in the pathophysiology of renal disease.
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PMID:Kidney angiotensin receptors and their role in renal pathophysiology. 1102 92

Angiotensin II (Ang II) infusion in rats augments vascular injury in balloon-injured carotid arteries and induces marked vascular and tubulointerstitial injury in kidneys. We examined how the AT1 receptor is modulated and whether blockade of the receptor with losartan could prevent the phenotypic and cellular changes. We also examined the role of the local renin-angiotensin system (RAS) by examining the expression of angiotensin-converting enzyme (ACE) and the effect of treatment with the ACE inhibitor, ramipril. Ang II infusion resulted in systemic hypertension and accelerated intimal and medial thickening in balloon-injured carotid arteries. Renal injury was manifested by proteinuria, glomerular phenotypic changes (mesangial expression of alpha-actin and podocyte expression of desmin), and tubulointerstitial injury with the tubular upregulation of the macrophage-adhesive protein, osteopontin, the interstitial accumulation of macrophages and myofibroblasts, and the deposition of collagen types III and IV. Ang II infusion decreased AT1 receptor number in the renal interstitium but not in glomeruli. Losartan completely blocked the Ang II-mediated hypertension, proteinuria, and injury to both carotid and kidney. Ang II infusion was also associated with an increase in ACE protein in both the proximal tubular brush border as well as at interstitial sites of injury, but despite evidence for activation of the local RAS, treatment with ramipril was without effect. These studies demonstrate that the renal and vascular injury induced by Ang II infusion is mediated by the AT1 receptor despite downregulation of the receptor in the interstitium. In addition, although there is evidence for local RAS activation, the injury appears to be mediated solely by the exogenous Ang II.
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PMID:Renal and vascular injury induced by exogenous angiotensin II is AT1 receptor-dependent. 1117 28

The mechanisms by which persistent proteinuria induces interstitial inflammation and fibrosis are not well known, although nuclear factor-kappaB (NF-kappaB), which regulates the transcription of many genes involved in renal injury, could be implicated. In rats with intense proteinuria, we studied the renal activation of NF-kappaB as well as the potential involvement of the vasoactive hormones angiotensin II (Ang II) and endothelin-1 (ET-1). Uninephrectomized Wistar-Kyoto rats receiving 1 g/d of BSA had proteinuria but no renal morphological lesions at day 1. By contrast, tubular atrophy and/or dilation and mononuclear cell infiltration were observed after 8 or 28 days of BSA administration, coinciding with maximal proteinuria. In relation to control uninephrectomized rats, the renal cortex of nephritic rats showed an increment in the activation of NF-kappaB at all time periods studied. By in situ Southwestern histochemistry, NF-kappaB activity was mainly localized in proximal tubules, interstitial mononuclear cells, and, to a lesser extent, the glomeruli. The administration of the ACE inhibitor quinapril plus the ET(A)/ET(B) receptor antagonist bosentan during 28 days to BSA-overloaded animals diminished proteinuria, renal lesions, and NF-kappaB activity more markedly than single drugs. Cultured tubular epithelial cells exposed to BSA revealed an intense NF-kappaB activation in a time- and dose-dependent manner. Incubation of cells with receptor antagonists of Ang II (AT(1): losartan and AT(2): PD-123,319) or ET-1 (ET(A): BQ123 and ET(B): IRL1038) inhibited significantly the BSA-induced NF-kappaB activity (90%, 75%, 90%, and 60% of inhibition versus basal, respectively). Our results show that overload proteinuria causes NF-kappaB activation in tubular epithelial cells both in vivo and in vitro. The vasoactive peptides Ang II and ET-1 appear to be implicated in this effect. The results reveal a novel mechanism of perpetuation of renal damage induced by persistent proteinuria.
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PMID:Activation of NF-kappaB in tubular epithelial cells of rats with intense proteinuria: role of angiotensin II and endothelin-1. 1130 20

Angiotensin-converting enzyme (ACE) inhibitors and AT1-receptor antagonists (ARAs) are widely administered to reduce urinary protein loss and slow the progression of proteinuric nephropathy to end-stage renal failure. Our group recently observed that the combination of ACE inhibitors and ARAs may have an additive antiproteinuric effect, which may occur because ACE inhibitors do not completely reduce angiotensin II (Ang II) production. Ang II is also produced by chymase. Thus, combination therapy better antagonizes the effects of Ang II. The purpose of this study is to ascertain whether the additive antiproteinuric effect of ACE inhibitors plus ARAs is dose dependent and related to the drug-induced reduction in systemic blood pressure. Therefore, enalapril (E; 10 mg/d) and losartan (LOS; 50 mg/d) were randomly administered alone and then in association; initial dosages were doubled when drugs were administered alone and in association. To determine the influence of the drug-dependent effect on reducing blood pressure and the reduction in urinary proteinuria, both ambulatory and office blood pressures were recorded. E and LOS administered alone reduced proteinuria by the same extent; no further reduction was observed when E and LOS alone were administered at a doubled dose. When E and LOS were coadministered, proteinuria decreased by a greater extent compared with E and LOS alone; an additional reduction in proteinuria was observed when combined therapy doses were doubled. The reduction in proteinuria was not correlated with clinical through blood pressure; however, reductions in diastolic and mean ambulatory blood pressures significantly correlated with the decrease in proteinuria, as well as with creatinine clearance. In conclusion, this study shows that combination therapy with E and LOS has an additive dose-dependent antiproteinuric effect that is likely induced by the drug-related reduction in systemic blood pressure. In normotensive proteinuric patients, it is likely that even a small reduction in systemic blood pressure may affect intraglomerular hemodynamics by a great extent because efferent arteriole regulation is hampered more completely by the coadministration of ACE inhibitors and ARAs.
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PMID:Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy. 1177 26

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