Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pharmacologic blockade of the renin and endothelin (ET) systems is an established strategy to interfere with progression of renal failure. In the Heyman nephritis model, additive benefits of decreases in BP with the combination of angiotensin-converting enzyme inhibitors (ACE-i) and ET(A) receptor antagonists (ET-RA) were demonstrated. To further investigate these findings and to exclude confounding effects of BP decreases, this issue was reassessed in a low-renin model of subtotal kidney resection. Subtotally nephrectomized (SNX) and sham-operated rats were left untreated or received an ACE-i, an angiotensin II subtype 1 receptor antagonist (AT1-RA), an ET-RA, or combinations thereof (ACE-i plus ET-RA or AT1-RA plus ET-RA). The parameters studied were the glomerulosclerosis index (GSI), tubulointerstitial index, vascular damage index, glomerular geometry, and albumin excretion. After 12 wk, BP values were comparable. Urinary albumin excretion rates were significantly higher for untreated SNX rats (24.3 +/- 31.3 mg/24 h), compared with untreated sham-operated rats (0.71 +/- 0.40 mg/24 h). Rates were significantly lower for all treated, compared with untreated, SNX groups. GSI values were significantly higher for untreated SNX rats than for untreated sham-operated rats. ACE-i caused significantly lower GSI in SNX rats (0.46 +/- 0.06), compared with AT1-RA (0.60 +/- 0.10) or ET-RA (0.65 +/- 0.10). GSI values were significantly decreased further with ACE-i plus ET-RA (0.29 +/- 0.09) or AT1-RA plus ET-RA (23 +/- 0.05) treatment. Changes in the tubulointerstitial index and vascular damage index proceeded in parallel. The results document BP-independent effects of the ACE-i and AT1-RA on the GSI and urinary albumin excretion and an effect of the ET-RA on the GSI. The contrasting results suggest different pathogenetic pathways for glomerulosclerosis and albuminuria. The combination of treatments provided superior effects on the GSI and tubulointerstitial index but not on urinary albumin excretion.
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PMID:Blood pressure-independent additive effects of pharmacologic blockade of the renin-angiotensin and endothelin systems on progression in a low-renin model of renal damage. 1172 25

Interventions to block the renin-angiotensin system (RAS) halt the progression of renal lesions in renal damage models. It has recently also been reported that established glomerulosclerosis can be reversed by pharmacologic blockade of the RAS. It was the aim of this study to confirm that high doses of angiotensin-converting enzyme (ACE) inhibitors reverse established glomerulosclerosis and to extend the findings by providing quantitative information on glomerular geometry, podocytes and other glomerular cells, renal vessels and tubulointerstitial tissue. Male Sprague Dawley rats were subjected to subtotal surgical renal ablation (SNX) (n = 27) or sham operation (n = 31) and fed using a pair-feeding protocol. Eight weeks after surgery, rats were either sacrificed or allocated to two arms: enalapril treatment (48 mg/kg body wt per day administered in the drinking fluid for 4 wk) or no treatment. Renal morphology was evaluated after 8 or 12 wk, respectively, by stereology in tissue fixed by pressure-controlled perfusion. Both systolic BP and albumin excretion rate were significantly higher in SNX compared with sham-operated controls. They were significantly reduced in SNX after delayed enalapril treatment. The glomerulosclerosis (GSI), tubulointerstitial (TII), and vascular (VI) damage indices were significantly higher in all SNX groups than in sham-operated controls. At the end of the experiment (12 wk after SNX) GSI, TII, and VI were significantly lower in SNX with delayed enalapril treatment (0.77 +/- 0.18, 0.63 +/- 0.19 and 0.43 +/- 0.16, respectively) compared with untreated SNX (1.64 +/- 0.14, 1.16 +/- 0.34 and 0.67 +/- 0.29, respectively). GSI, TII, and VI were also significantly lower in SNX with delayed enalapril treatment compared with SNX sacrificed without treatment 8 wk after SNX. The same was true for glomerular volume. The number of podocytes was not affected by SNX, but podocyte volume was increased. Both indices remained unaffected by treatment. The numbers of cells within the mesangium and endothelial cells per glomerulus were significantly lower in SNX after delayed enalapril treatment compared with untreated SNX. These results strongly suggest regression of preexisting lesions, i.e., glomerular, tubular, and vascular remodeling as well as reversal of glomerular hypertrophy by ACE inhibitor treatment. The study confirms that high-dose ACE inhibitor treatment causes partial reversal of glomerular as well as interstitial lesions in subtotally nephrectomized rats.
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PMID:Reversal of glomerulosclerosis after high-dose enalapril treatment in subtotally nephrectomized rats. 1456 93

Angiotensin II accelerates and renin-angiotensin system blockade halts progression; blockade with high doses even reverses established glomerulosclerosis. Aldosterone also accelerates progression of glomerulosclerosis, partially independently of angiotensin II. The purpose of this study was to assess the relative ability of an angiotensin receptor type 1 (AT1) blocker, a mineralocorticoid receptor blocker, and their combination to reverse glomerulosclerosis. Sprague-Dawley rats were subjected to subtotal renal ablation (SNX) or sham operation. Eight weeks after surgery, they were either euthanized or allocated to treatment with vehicle, losartan, spironolactone, their combination, or unspecific antihypertensive treatment (dihydralazine) for 4 wk. Renal morphology was evaluated by stereology in tissues obtained using pressure-controlled perfusion fixation. Systolic blood pressure was significantly higher in SNX compared with sham-operated animals and decreased in all treatment groups. Compared with wk 8 after SNX, the glomerulosclerosis index (GSI) had increased further by week 12 in the vehicle- and dihydralazine-treated groups but was significantly lowered in the SNX+losartan as well as in the SNX+losartan+spironolactone groups and had not progressed further in the SNX+spironolactone group. The study confirms the partial regression of established glomerulosclerosis in subtotally nephrectomized rats after high-dose AT1 receptor blockade. Nonhyperkalemic doses of spironolactone prevented the increase but failed to decrease the GSI below the 8-wk level and preserved podocyte numbers. Combining the AT1 blocker with mineralocorticoid receptor blockade failed to further increase the regression of glomerulosclerosis.
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PMID:Regression of glomerulosclerosis in subtotally nephrectomized rats: effects of monotherapy with losartan, spironolactone, and their combination. 1843 88

Cardiac remodelling with interstitial fibrosis in renal failure, which so far is only poorly understood on the molecular level, was investigated in the rat model by a global gene expression profiling analysis. Sprague-Dawley rats were subjected to subtotal nephrectomy (SNX) or sham operation (sham) and followed for 2 and 12 weeks, respectively. Heart-specific gene expression profiling, with RZPD Rat Unigene-1 cDNA arrays containing about 27 000 gene and EST sequences revealed substantial changes in gene expression in SNX compared to sham animals. Motor protein genes, growth and differentiation markers, and extracellular matrix genes were upregulated in SNX rats. Obviously, not only genes involved in cardiomyocyte hypertrophy, but also genes involved in the expansion of non-vascular interstitial tissue are activated very early in animals with renal failure. Together with earlier findings in the SNX model, the present data suggest the hypothesis that the local renin-angiotensin system (RAS) may be activated by at least two pathways: (a) via second messengers and Gproteins (short-term signalling); and (b) via motor proteins, actins and integrins (longterm signalling). The study documents that complex hybridization analysis yields reproducible and promising results of patterns of gene activation pointing to signalling pathways involved in cardiac remodelling in renal failure. The complete array data are available via http://www.rzpd.de/cgi-bin/services/exp/viewExpressionData.pl.cgi.
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PMID:Gene expression profiling on global cDNA arrays gives hints concerning potential signal transduction pathways involved in cardiac fibrosis of renal failure. 1862 21