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

Angiomyolipoma occurs rarely in the liver, with only 25 previous cases being reported in the English literature. The article describes two additional cases, one of which was multicentric, with results of ultrastructural and immunocytochemical studies. Many of the tumor cells contained numerous electron-dense granules, some with transverse striations like those found in melanosomes. Both tumors stained positively for S-100 protein and melanoma-specific antibody HMB-45. One case also expressed vimentin and neuron-specific enolase. Both were negative for cytokeratin, carcinoembryonic antigen, alpha-fetoprotein, desmin, muscle-specific actin, factor VIII antigen, and chromogranin. Comparison of our ultrastructural findings with those of classic renal angiomyolipoma raises the possibility that the melanosomelike structures may represent renin granules rather than melanosomes, although the latter are not excluded. Expression of HMB-45 in angiomyolipoma has important biologic and diagnostic implications, whether or not it reflects melanocytic differentiation.
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PMID:Hepatic angiomyolipoma with striated granules and positivity with melanoma--specific antibody (HMB-45): a report of two cases. 175 13

Mesenchymal renal tumors in F-344 newborn rats were induced by a single dose of dimethylnitrosamine. The induced tumors were successfully transplanted into adult rats under the renal capsule. Neither the primary nor the transplanted neoplasms from various generations of grafts changed their morphological features during the tumor passage, having the same cellularity with high mitotic activity and the tendency to invade the host kidney rapidly. On the basis of lectin histochemistry and immunohistology, the tumor proved to be a mesenchymal neoplasm without any obvious capacity of the proliferating cells to differentiate into any well-known organoid element normally found in mature renal parenchyma. However, the proliferating neoplastic cells were found to have a strong vimentin positivity with desmin expression. Ultrastructurally, myofilaments with attachment bodies characteristic of smooth muscle cells were generally present in various amounts in many tumor cells. In addition, on the basis of the physiological data and on kidney/tumor renin activity obtained, it is interesting to note that the tumor-graft-invaded kidneys retained their enzyme activity, despite the obvious loss of renal tissue including glomeruli. However, the immunohistochemical findings with anti-renin antibody have clearly shown that this is not due to a renin-producing tumor but rather to the surviving (probably) non-neoplastic arterioles retaining the capacity to produce renin. Although these arterioles have mostly been found next to necrotic areas, commonly occurring in dimethylnitrosamine-induced transplantable renal tumors, the question of a possible physiological role of renin in tumor necrosis or in angiogenesis has remained open.
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PMID:Morphological and immunohistochemical characteristics of dimethylnitrosamine-induced malignant mesenchymal renal tumor in F-344 rats. 214 98

Angiotensin II (AII) is a vasoconstrictive peptide with hypertrophic and mitogenic effects on many cell types. Previous studies have shown that in vivo administration of AII in rats results in proliferation of, and phenotypic changes in, many renal cell populations, but in doses also causing hypertension. Thus, it was not possible to differentiate nonhemodynamic from hypertensive effects of AII. Therefore, we studied rats with renin-dependent, AII-mediated hypertension (the two-kidney, one-clip Goldblatt model; mean systolic blood pressure 238 +/- 48 v 140 +/- 6 mm Hg in sham-operated controls). The unclipped kidneys, which were exposed to high blood pressure, developed significant glomerular and tubulointerstitial injury, tubulointerstitial cell proliferation, dense focal interstitial monocyte-macrophage influx, increased deposition of types I and IV collagen, as well as increased cellular expression of desmin and actin, in tubulointerstitial areas when examined at 11 weeks. In contrast, clipped kidneys, protected from hypertension but with high local renin expression, had minimal abnormalities. These studies suggest that in this model increased renin, and presumably AII, does not mediate significant proliferative or phenotypic changes in the kidney in the absence of hypertension at 11 weeks.
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PMID:Renal proliferative and phenotypic changes in rats with two-kidney, one-clip Goldblatt hypertension. 817 53

The binding of antibodies to podocytic antigens such as the Heymann antigen or aminopeptidase A may lead to the induction of a membranous glomerulonephritis in several species. To study the possible future interactions of antibodies with antigens on these podocytes, epithelial cells from isolated mouse glomeruli were cultured. By indirect immunofluorescence, the cells were positive for cytokeratin, vimentin, desmin, and the ZO-1 protein, a component of the tight junction complex. When rat monoclonal antibodies were used, the cells were also positive for the hydrolases aminopeptidase A and dipeptidyl peptidase IV, and they stained with ASD-33, a monoclonal antibody that recognized an epitope only present on the cell membranes of mouse podocytes. They were negative for the von Willebrand factor and did not stain with a monoclonal antibody (ASD-13) that binds to endothelial cells of glomeruli and peritubular capillaries. By electron microscopy, the cells showed tight junctions but lacked Weibel Palade bodies (endothelium), desmosomes, and cilia (parietal epithelium). The mRNA expression of several components of the renin-angiotensin system was also examined, and some factors indirectly coupled to the renin-angiotensin system component angiotensin II in this podocytic culture by RT-PCR analysis. mRNA Expression for the angiotensin II degrading hydrolase aminopeptidase A and angiotensinogen was found, but this was not found for any other component of this system, such as renin, angiotensin-converting enzyme, or the angiotensin II receptors AT1a, AT1b, and AT2. Low mRNA expression for dipeptidyl peptidase IV was observed. In addition, expression of the growth factors transforming growth factor-beta and interleukin-7, and the extracellular matrix components fibronectin, laminin B2, perlecan, and collagen IV alpha 1, was observed. Given these characteristics, a glomerular epithelial cell culture with features of podocytes in vivo that will allow future studies on the interaction of anti-aminopeptidase A monoclonal antibodies and angiotensin II with aminopeptidase A was established. This is of interest in light of the observation that injection of mice with anti-aminopeptidase A antibodies causes an acute albuminuria.
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PMID:Mouse glomerular epithelial cells in culture with features of podocytes in vivo express aminopeptidase A and angiotensinogen but not other components of the renin-angiotensin system. 917 40

Nephrotoxicity of CyA was analyzed histologically in rats fed a low-sodium diet. CyA was subcutaneously administered daily at a dose of 15 mg/kg for 10 or 35 days with or without prior uninephrectomy (UNT) in male Sprague-Dawley rats receiving a low-sodium diet (0.03% sodium). CyA-administered rats showed impaired renal function as well as tubulo-interstitial lesions, such as edema, tubular basement membrane changes, and tubular atrophy, in the cortex, especially in the subcapsular portion, within 10 days. On day 35, the tubulo-interstitial lesions were advanced with mild focal interstitial fibrosis. These lesions were mild in the UNT group compared to the non-UNT group. Immunohistochemically, CyA treatment caused an increase in number of renin-positive cells in the afferent arteriolar wall at juxtaglomerular area. These cells lost the expression of calponin, which is a marker of mature smooth muscle cells. In addition, in afferent arterioles and interlobular arteries, electron-dense fibrous bodies were found in the smooth muscle cells on days 10 and 35. Immunoelectron microscopically, these bodies showed scattered positive staining for calponin and alpha-actinin, were negative or only peripherally positive for alpha-SMA and vimentin, and were completely negative for desmin. This study revealed that CyA could cause interstitial lesions starting in the subcapsular portion of the renal cortex and vascular lesions of the preglomerular artery. Increases in number of renin granules and formation of cytoplasmic fibrous bodies in smooth muscle cells could be the forerunner of severe arteriolar wall damage.
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PMID:CyA-mediated renal interstitial and vascular lesions in the rat under low-sodium diet. 1093 37

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

Denys-Drash syndrome (DDS) is caused by dominant mutations of the Wilms' tumour suppressor gene, WT1, and characterized by a nephropathy involving diffuse mesangial sclerosis, male pseudohermaphroditism and/or Wilms' tumourigenesis. Previously, we reported that heterozygosity for the Wt1tmT396 mutation induces DDS in heterozygous and chimeric (Wt1tmT396/+<-->+/+) mice. In the present study, the fate of Wt1 mutant cells in chimeric kidneys was assessed by in situ marker analysis, and immunocytochemistry was used to re-examine the claim that glomerulosclerosis (GS) is caused by loss of WT1 and persistent Pax-2 expression by podocytes. Wt1 mutant cells colonized glomeruli efficiently, including podocytes, but some sclerotic glomeruli contained no detectable Wt1 mutant cells. The development of GS was preceded by widespread loss of ZO-1 signal in podocytes (even in kidneys where <5% of glomeruli contained Wt1 mutant podocytes), increased intra-renal renin expression, and de novo podocyte TGF-beta1 expression, but not podocyte Pax-2 expression or loss of WT1, synaptopodin, alpha-actinin-4 or nephrin expression. However, podocytes in partially sclerotic glomeruli that still expressed WT1 at high levels showed reduced vimentin expression, cell cycle re-entry, and re-expressed desmin, cytokeratin and Pax-2. The results suggest that: (i) GS is not due to loss of WT1 expression by podocytes; (ii) podocyte Pax-2 expression reflects re-expression rather than persistent expression, and is the consequence of GS; (iii) GS is mediated systemically and the mechanism involves activation of the renin-angiotensin system; and (iv) podocytes undergo typical maturational changes but subsequently de-differentiate and revert to an immature phenotype during disease progression.
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PMID:Murine Denys-Drash syndrome: evidence of podocyte de-differentiation and systemic mediation of glomerulosclerosis. 1291 83

Angiotensin II (AngII) plays an important role in renal damage by acting on hemodynamics, cell-growth, proliferation, and fibrosis, mainly by effects on the AngII type 1 (AT(1)) receptor. The AT(1) receptor activates several intracellular signaling molecules such as mitogen-activated protein kinases extracellular signal-regulated kinase (ERK) and p38, but their role in AngII-mediated renal damage is not well characterized. We therefore investigated whether pharmacologic blockade of ERK and p38 could prevent renal damage in high-renin homozygous transgenic rats (Ren2), with the effects of an AT(1) receptor antagonist (AT(1)-RA) as a reference. Seven-week-old homozygous Ren2 rats were treated with low-dose AT(1)-RA candesartan, ERK inhibitor tyrphostin, or p38 inhibitor SB239063 for 4 weeks. Untreated Ren2 and SD rats served as controls. Blood pressure was measured at 7 and 11 weeks. At 11 weeks, plasma renin activity (PRA) and serum aldosterone were determined, and the animals were killed. Kidney sections were scored for glomerular and interstitial smooth muscle actin and glomerular desmin expression as early markers for renal damage. Mesangial matrix expansion was determined as a marker for structural damage. PRA and aldosterone levels were elevated in untreated Ren2 rats in comparison to SD controls. AT(1)-RA further increased PRA but decreased aldosterone. All parameters of renal damage were elevated in untreated Ren2 rats. Blood pressure was not elevated at week 7 in Ren2 and not affected by either treatment. Mild signs of hypertensive damage were found in untreated Ren2 rats. All interventions significantly diminished damage to glomerular epithelium and interstitium. In addition, AT(1) receptor and p38 blockade reduced mesangial matrix expansion. In homozygous Ren2 rats, renal damage was ameliorated by a nonhypotensive dose of an AT(1)-RA and, similarly, by blockade of ERK or p38. This suggests that ERK and p38 are involved in AngII-mediated renal damage.
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PMID:Specific MAP-kinase blockade protects against renal damage in homozygous TGR(mRen2)27 rats. 1469 Dec 94

Inhibition of the renin angiotensin aldosterone system (RAAS) produces protective effects on cardio-renal injury in type 2 diabetes. Vasopeptidase inhibitors (VPI) represent a new pharmacological tool, acting by simultaneous inhibition of the RAAS and neutral endopeptidase. We examined the effects of chronic VPI on renal function and morphology in experimental type 2 diabetes as compared to angiotensin converting enzyme inhibition (ACE-I). Zucker diabetic fatty rats aged 13 weeks were treated with either VPI (AVE7688, ZDF-VPI, n = 8) or ACE-I (Ramipril, ZDF-ACE-I, n = 7) or placebo (ZDF, n = 8). Heterozygous rats served as non-diabetic controls (Ctr, n = 8). Both treatments led to a similar decrease in blood pressure. After 10 weeks of treatment, ZDF developed marked albuminuria. The latter was significantly attenuated in ZDF-VPI as compared to ZDF and ZDF-ACE-I. Renal histology revealed a significant expansion in the glomerular tuft area in all ZDF groups. However, expression of glomerular desmin, which has been recognized as a sensitive marker of early podocyte damage, was significantly increased in ZDF as compared to Ctr. Desmin was reduced in ZDF-VPI but not in animals treated with ACE-I. There was a correlation between albumin excretion and desmin-positive glomerular area. In experimental type 2 diabetes, albuminuria correlates to podocyte damage. These hallmarks of diabetic nephropathy are attenuated by VPI to a greater extent than by ACE-I alone. These findings suggest that podocyte damage is an early critical step in the progression of diabetic nephropathy, and that VPI is a promising pharmacological tool in the treatment of diabetic renal disease.
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PMID:Vasopeptidase inhibition attenuates proteinuria and podocyte injury in Zucker diabetic fatty rats. 1733 28

1. The present study was performed to test the hypothesis that the reactive oxygen species (ROS)-angiotensinogen (AGT)-renin angiotensin system (RAS) axis is sequentially activated in the development of diabetic nephropathy in Zucker diabetic fatty (ZDF) obese rats. 2. Genetic pairs of male ZDF obese and control ZDF lean rats (n = 12 of each species) were killed every 3 weeks from 12 to 21 weeks of age (n = 6 at each time point). 3. The ZDF obese rats developed diabetes mellitus at 12 weeks. At that time, urinary excretion rates of 8-isoprostane were similar between the groups; however, urinary 8-isoprostane levels were significantly increased at 15 weeks in ZDF obese rats compared with controls (36 +/- 6 vs 15 +/- 2 ng/day, respectively). At 15 weeks, protein levels of cortical angiotensinogen were similar between groups; however, cortical angiotensinogen levels were significantly increased at 18 weeks in ZDF obese rats compared with controls (relative ratio of 2.32 +/- 0.21 vs 1.00 +/- 0.20, respectively). At 12 weeks, angiotensin (Ang) II-like immunoreactivity was similar between groups in both the glomeruli and tubules; however, AngII-like immunoreactivity was increased significantly at 21 weeks in ZDF obese rats compared with controls (relative ratios of 1.98 +/- 0.55 vs 1.00 +/- 0.03, respectively, for glomeruli and 1.58 +/- 0.16 vs 1.00 +/- 0.13, respectively, for tubules). Moreover, at 21 weeks, the desmin-positive area in the glomeruli (0.63 +/- 0.08 vs 0.22 +/- 0.05%) and Masson's trichrome stain-positive area in the interstitium (4.97 +/- 0.05 vs 3.18 +/- 0.41%) were significantly increased in ZDF obese rats compared with controls, even though these differences had not been observed earlier. 4. These data suggest that the sequential activation of the ROS-AGT-RAS axis plays an important role in the development of diabetic nephropathy in ZDF obese rats.
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PMID:Sequential activation of the reactive oxygen species/angiotensinogen/renin-angiotensin system axis in renal injury of type 2 diabetic rats. 1843 60


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