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)

A transplantable tumour, designated NB-Y, was established from a spontaneous nephroblastoma in an F344 rat. NB-Y was serially passaged in syngeneic rats by subcutaneous implantation up to the 49th generation. The transplants grew into nodules with an average diameter of 5 cm and average weight of 92.9 g 4 weeks after implantation. The primary tumour and NB-Y consisted mainly of sheets or clusters of undifferentiated blastemal cells, which reacted immunohistochemically for vimentin but not for keratin. Renin-containing cells were observed in the small blood vessel walls within the primary tumour, but neoplastic cells of both primary tumour and NB-Y failed to stain for renin. Plasma renin activity was significantly higher (40.7 ng per ml per h) in transplanted rats 4 weeks after implantation compared with non-transplanted controls (28.0 ng per ml per h). Hyperplastic juxtaglomerular cells were often observed in rats bearing NB-Y. Sinusoidal dilatation was present in the liver, adrenal glands, pituitary gland and bone marrow of recipients, suggesting abnormal blood flow provoked via the renin-angiotensin system. The present study revealed the development of hyper-reninaemia in NB-Y-bearing rats, but its pathogenesis remains unknown.
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PMID:Morphological characteristics of a transplantable nephroblastoma (NB-Y) in F344 rats and the relation of tumour growth to hyper-reninaemia in NB-Y-bearing rats. 133 Dec 9

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

Chronic cyclosporine (CsA) nephrotoxicity is a major complication of solid organ transplantation, and is characterized histologically by striped tubulointerstitial fibrosis, tubular atrophy, and hyalinization of the afferent arteriole, a highly specific finding in cyclosporine injury. The salt-depleted rat model of chronic cyclosporine nephropathy mimics these lesions in humans. We conducted sequential studies of this model in groups of pair fed rats (N = 6) treated with CsA (15 mg/kg, s.q.) or an equivalent dose of olive oil. Proliferation of tubular and interstitial cells was documented early in the medulla by day 5 (3.2 +/- 2.1 vs. 0.81 +/- 0.4 cells/HPF in CsA vs. control, P < 0.02), and was maximal in areas of interstitial fibrosis by day 35 (7.9 +/- 3.7 vs. 0.52 +/- 0.2 cells/HPF in CsA vs. control, P < 0.005). The interstitial fibrosis was associated with a significant macrophage influx by day 35 (13.9 +/- 3.5 vs. 1.5 +/- 0.32 cells/HPF, CsA vs. control, P < 0.005), which correlated with increased cortical tubular staining for the macrophage adhesion protein, osteopontin. Elevated serum creatinine correlated with interstitial fibrosis at day 35 (0.85 +/- 0.11 vs. 0.40 +/- 0.03 mg/dl Cr, CsA vs. control, P < 0.005) by linear regression (r = 0.9, P < 0.05). Medullary proliferation and interstitial fibrosis correlated with decreased tubular concentrating ability, and higher urinary volume. Cortical interstitial fibrosis was maximal at day 35 and was associated with an increase in type I and type IV collagen deposition, while tubular injury was associated with increased vimentin expression. Tubular interstitial cells also expressed increased vimentin early in the medulla (day 10) and later in the cortex. Both groups remained normotensive despite significantly elevated juxtaglomerular (JG) apparatus renin expression in CsA treated animals, implicating the intrarenal-renal renin-angiotensin system in this disease. We conclude that cyclosporine nephrotoxicity is associated with early tubular and interstitial cell proliferation, and a significant macrophage influx that precedes the development of cortical interstitial fibrosis and afferent arteriolar hyalinosis. These early cellular changes correlate with functional abnormalities including decreased creatinine clearance (CCr) and decreased medullary concentrating ability, which stabilized despite progressive fibrosis. These cellular events may be important in the pathogenesis of chronic CsA nephrotoxicity.
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PMID:Cellular proliferation and macrophage influx precede interstitial fibrosis in cyclosporine nephrotoxicity. 756 11

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

We examined the role of angiotensin in renal remodeling that is specifically channeled through the angiotensin type 2 receptor (AT2 receptor). Previously, we observed that in mouse embryonic kidneys the AT2 mRNA is predominantly expressed in the mesenchyme. We therefore chose a model of unilateral ureteral obstruction, characterized by activation of the renin-angiotensin system, while fibrosis develops prominently within the renal interstitium. Male wild-type mice (Agtr2 -/Y) and mice null mutant for the AT2 gene (Agtr2 -/Y) were subjected to a complete unilateral ureteral ligation for 5 or 14 days. Obstructed kidneys of Agtr2 -/Y mice showed more severe interstitial fibrosis than those of Agtr2 +/Y mice, confirmed by increased collagen by point-counting on Masson trichrome stained sections, and increased alpha 1(I) collagen mRNA expression by Northern blot. Immunohistochemistry staining for PCNA (a marker of cell proliferation), F4/80 (a marker of macrophages), vimentin (a marker of fibroblasts), and alpha SMA (a marker of myofibroblasts) revealed that, while the two groups were comparable in the degree of cell proliferation and macrophage infiltration, fibroblasts/ myofibroblasts were present in a greater abundance in obstructed kidneys of Agtr2 -/Y mice than in Agtr2 +/Y at both 5 and 14 days after obstruction. Moreover, cells undergoing apoptosis were significantly less in Agtr2 -/Y than in Agtr2 +/Y. Thus, the AT2 receptor significantly impacts the remodeling process within renal interstitium, potentially by regulating the population of collagen-producing cells.
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PMID:Accelerated fibrosis and collagen deposition develop in the renal interstitium of angiotensin type 2 receptor null mutant mice during ureteral obstruction. 955 1

Recent evidence indicates that tubulointerstitial injury plays an important role in hypertensive kidney injury and that phenotypic changes contribute to this pathology. Moreover, angiotensin II is known to be actively involved in the pathogenesis of progressive kidney injury induced by hypertension. The present study was undertaken to see the effect of a newly developed angiotensin II type I receptor (AT1 receptor) antagonist on hypertension-induced kidney injury and to determine the contribution of phenotypic changes to morphologic alterations. Two-kidney, one-clip (2K1C), Goldblatt hypertensive rats (n = 27) were made by clipping the left renal artery. These animals were orally administered 57G709 (a selective non-peptide AT1 receptor antagonist)(10 mg/kg/day), captopril (20 mg/kg/day), or vehicle alone for 23 days beginning 4 weeks after clipping. In the non-clipped kidney of vehicle-treated 2K1 C rats, marked tubulointerstitial injury as well as glomerular sclerosis and/or hyalinosis was found in association with phenotypic changes, as shown by the neoexpression of vimentin in periglomeruli, perivascular walls, distal tubuli, and injured interstitium. Renin expression was markedly suppressed in the non-clipped kidneys of vehicle-treated 2K1C rats as compared with renin expression in normotensive control kidneys of sham-operated rats. Both 57G709 and captopril markedly ameliorated hypertensive kidney injury as reflected by the glomerular sclerosing index and by the tubulointerstitial index as determined by the point-counting method, and this improvement was accompanied by a significant decrease in blood pressure, urinary protein excretion, kidney/body weight ratio, and heart/body weight ratio. In addition, the vimentin neoexpression mentioned above was also suppressed with an inhibition of angiotensin II. These results suggest that in 2K1C Goldblatt hypertensive kidney injury, the AT1 receptor antagonist 57G709 exerts a potent renal protective effect associated with the inhibition of phenotypic changes.
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PMID:Angiotensin II receptor blockade limits kidney injury in two-kidney, one-clip Goldblatt hypertensive rats with special reference to phenotypic changes. 998 65

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

Recently, the renin-angiotensin system (RAS) was implicated in organ fibrosis. However, few studies have examined the localization of RAS components, such as angiotensin II receptors, renin (REN), angiotensinogen (AGTN), and angiotensin-converting enzyme (ACE), in the fibrosing kidney. To localize these components in the fibrosing kidney, we used a murine model of renal fibrosis that shows an enhanced expression of angiotensin II type 1A receptor (AT(1A)R) and AGTN. Our results indicate that the overall expression of angiotensin II type 2 receptor (AT(2)R) and ACE was attenuated in this model, whereas REN expression was unchanged. In addition to tubular epithelial cells that were positive for AT(1A)R, AT(2)R, REN, and AGTN, interstitial fibroblast-like cells expressed AT(1A)R, REN, AGTN, and ACE in the fibrosing kidney. The interstitial fibroblast-like cells that were positive for AT(1A)R mRNA were further characterized as positive for the expression of vimentin and transforming growth factor-beta1. These data provide strong evidence for a tubulointerstitial RAS within the fibrosing kidney, and a linkage between the RAS and renal fibrogenesis.
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PMID:Interstitial fibroblast-like cells express renin-angiotensin system components in a fibrosing murine kidney. 1189 Nov 74

Angiotensin II and insulin-like growth factor-I (IGF-I) are known to be actively involved in the pathogenesis of progressive renal injury, particularly in cell proliferation and phenotypic changes that contribute to tubulointerstitial injury. To investigate the possible mechanisms by which angiotensin II type 1 receptor antagonist (AIIA) ameliorates renal injury in a renal ablation model and to determine the contribution of phenotypic changes and IGF-I to morphological changes, we examined 1) whether AIIA attenuated phenotypic changes as markers of alpha-smooth muscle actin (SMA) and vimentin, 2) whether AIIA altered renal IGF-I expression, and 3) the changes of tubulointerstitial cell kinetics between apoptosis (tested via terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling, TUNEL) and cell proliferation (a test of proliferating cell nuclear antigen, PCNA). Following a sham operation (sham) or 5/6 nephrectomy (Nx), we administered E4177, a potent, selective competitive angiotensin II type 1 receptor antagonist (AIIA), for 10 weeks. In Nx rats, SMA and vimentin expressions developed in injured tubulointerstitium, particularly in hypoperfused scar-adjacent areas, and there was an increase in renal IGF-I expressions. The TUNEL score increased 5-fold and PCNA increased 8-fold, compared with TUNEL and PCNA measurements in sham-operated rats. Renin expression in the juxtaglomerular apparatus was markedly suppressed in the Nx group, although de novo tubular renin expression appeared in Nx, compared with that in the sham group. E4177, both 10 mg/kg (AIIA 10) and 1 mg/kg (AIIA 1), markedly ameliorated renal injury, although blood pressure was less affected in AIIA 1. Both AIIA 10 and AIIA 1 suppressed the neoexpressions of SMA and vimentin in an association with decreased IGF-I expression. Regarding cell kinetics, neither AIIA 10 nor AIIA 1 decreased the TUNEL score; rather, tended to increase, while PCNA was significantly suppressed by AIIA. In conclusion, one of the underlying protective mechanisms of AIIA in this model may be related to the modulations of angiotensin II-induced phenotypic changes and tubulointerstitial cell kinetics through IGF-I.
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PMID:Angiotensin II and IGF-I may interact to regulate tubulointerstitial cell kinetics and phenotypic changes in hypertensive rats. 1204 42


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