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Background: Young (4 week) spontaneously hypertensive rats (SHR) exhibit greater renal responses to angiotensin II (Ang II) than normotensive Wistar Kyoto (WKY) rats. SHR pups cross-fostering to a WKY dam at birth (SHRX) are less sensitive to Ang II and have lower adult blood pressure. The aim of this study was to compare renal renin-angiotensin system activity in young naturally reared and cross-fostered SHR pups., Methods: SHR and WKY rats were reared either by their natural mothers or by a foster mother of the opposite strain. At 5, 10, and 15 days of age, renal tissue renin activity and Ang II concentration were measured by radioimmunoassay. Renin-secreting cells were identified by in situ hybridization and AT(1) receptor expression was compared using Western blots. Ang II-mediated cAMP generation was measured in isolated proximal tubules., Conclusions: Tissue renin activity and numbers of renin-secreting cells did not differ, but Ang II was higher in SHRX. The AT(1) receptor expression was significantly lower in SHRX compared with SHR. Basal and Ang II-stimulated cAMP was lower in SHR tubules compared with WKY and SHRX tubules.Cross-fostering reversed the increased renal sensitivity of the SHR to Ang II. These data suggest that renal AT(1) receptor expression can be manipulated during the postnatal period and that this may affect adult blood pressure.

Twin-twin transfusion syndrome (TTTS) complicates one in five monochorionic pregnancies and is generally associated with high mortality and morbidity. One twin (the recipient) grows appropriately and has polyhydramnios while the other (the donor) may have a reduced growth velocity and severe oligohydramnios. The disparities in amniotic fluid volumes represent differences in fetal urine output. These differences occur secondary to hemodynamic changes, in which the vascular arrangement of placental anastomoses in TTTS leads to unidirectional flow from the donor to the recipient twin. A better understanding of the pathophysiology may contribute to improved management of this morbid condition. We studied three consecutive prospectively diagnosed stillborn twin pairs affected by early-onset TTTS. Renin gene expression was studied in sections of fetal kidneys with immunocytochemistry using a renin antiserum and with in situ hybridization using riboprobes complementary to renin mRNA, and renin-secreting cells (RCC) were counted. The overall maturation of the renal cortex was assessed by the percentage of immature glomeruli. The donor twin kidneys were smaller than those of the recipients, but the maturation of the renal cortex was not significantly different (28.2% immature glomeruli in the donor and 24.4% in the recipient kidney). The donor kidney showed increased renin gene expression with hyperplastic juxtaglomerular apparatuses (JGAs) that contained excess RCCs (median 20.02 [25th-75th centiles, 5.4, 25.1 RCCs per 100 glomeruli]). In contrast, the recipient kidney was virtually devoid of these cells (0.04 [0, 0.36] RCCs per 100 glomeruli; P < 0.05). In the donor kidney, increased renin release may, by a local action, contribute to renal vasoconstriction and oliguria. Increased renin and/or angiotensin II in the blood passing through the placental anastomoses may, by an endocrine action, suppress renin synthesis in the recipient kidney, thereby increasing renal blood flow and causing polyuria and polyhydramnios. These changes in the renal RAS could thus contribute to the pathogenesis of TTTS. The renal renin changes noted here may represent a contributory or compensating mechanism, the success of which may dictate the overall survival of the twin pregnancy and allow better understanding of the pathophysiology and perhaps therapy that may be employed in this condition.

Airway remodelling occurs in chronic asthma. Angiotensin II promotes growth in cardiovascular remodelling. Since the renin-angiotensin system is activated in acute severe asthma, we hypothesized that angiotensin II has a role in airway remodelling. A total of 14 young male Wistar rats were randomly divided into two groups. All received 2-week infusions of bromodeoxyuridine, and the experimental group also received angiotensin II. Blood pressure rose in the angiotensin II-infused group [mean levels: pre-infusion, 134.9 (S.D. 14.7) mmHg; post-infusion, 197.1 (22.5) mmHg], and expression of renin mRNA in the renal juxtaglomerular cells was suppressed in these animals. The proportion of bromodeoxyuridine-positive cell nuclei was no different in the airways of control and angiotensin II-infused animals for smooth muscle [mean bromodeoxyuridine index: control, 8. 6% (S.E.M. 1.1%); angiotensin II, 9.3% (1.1%)], epithelium [control, 16.7% (2.3%); angiotensin II, 16.0% (2.2%)] and adventitia [control, 26.4% (2.2%); angiotensin II, 26.6% (2.4%)]. In the arteries, bromodeoxyuridine indices were higher in the angiotensin II-infused rats [18.4% (2.3%)] than in the control animals [9.4% (2.8%)], but no difference was found in the veins [12% (2.9%) and 11.4% (2.6%) respectively]. Morphometry of the airway wall and mesenteric vasculature was no different in the two groups. Therefore a 2-week infusion of angiotensin II increases blood pressure and DNA synthesis in the mesenteric arteries, but does not cause airway remodelling, in the rat.

Background: Intrauterine growth restriction (IUGR) has been linked to impaired renal function and hypertension, suggesting that an adverse prenatal environment could alter kidney development and renin production., Methods: Immunohistochemistry and in situ hybridization were employed to localize renin-containing cells (RCCs) in the deep, middle, and superficial zones of autopsy kidney sections, in parallel with histologic maturation, from unexplained stillborn fetuses of normal weight (N = 26) and stillborn fetuses with IUGR (N = 17)., Results: In the control group, the number of RCC per 100 glomeruli in the deep zone decreased with advancing gestation from 40 at 20 weeks gestation to five at term (P < 0.001), whereas the opposite change was found in the superficial zone (increase from 5 per 100 to 55 per 100; P < 0.001). In the IUGR group, the density of RCCs in both the superficial and deep zones was similar to the control group at 20 weeks, and no shift in renin gene expression was observed as gestation advanced. Histologic maturation was unaltered., Conclusions: Renin gene expression persists and predominates in the deep renal cortex of the stillborn IUGR fetus, and could contribute to the pathogenesis of neonatal oliguria and/or hypertension during postnatal life.

Human glomerular capillary tufts were removed by microdissection and scanning electron microscopy was used to examine the surface of the capillary tuft and the interior of its Bowman's capsule in order to identify connections between the tuft and capsule. Glomeruli were examined in histologically normal renal cortex from 12 kidneys removed for tumour and 12 renal allografts removed for end-stage rejection. In normal kidney, the glomerular tuft was connected to Bowman's capsule by single podocytes and their processes. At the vascular pole, these were predominantly associated with parietal podocytes which lined Bowman's capsule. At the tubular pole, occasional podocytic processes derived from the capillary tuft bridged Bowman's space and connected to Bowman's capsule where there were no parietal podocytes. These podocytic connections were also found in all rejected transplants, but in addition adhesions were identified which consisted of thicker connections between the tuft and capsule. At the vascular pole, tuft-to-capsule adhesions were found in all 12 kidneys; these were always associated with parietal podocytes. Tubular pole adhesions were identified in ten of the 12 transplants. They were associated with abnormal squamous cells, but not with parietal podocytes. When the capillary tuft herniated into the proximal tubule, the tuft sometimes formed an adhesion with the origin of the proximal tubule. These observations suggest that podocyte connections between the glomerular tuft and Bowman's capsule may be precursors of glomerular adhesions at the vascular pole. Since tuft-to-capsule adhesions at the vascular pole differ morphologically from those at the tubular pole, this may reflect different pathogenetic mechanisms at the opposite poles of the glomerulus.

A 67-year-old woman presented with dry skin, facial hair, hoarse voice, and weight gain. She was hypertensive (168/ 96 mm Hg), her haemoglobin concentration was 19 g/l, and haematocrit was 55.7%. The diagnosis of probable secondary polycythaemia was made. Blood testosterone concentration was 44 nmol/l (normal < 5) and was not suppressed by dexamethasone, suggesting a neoplastic source rather than a pituitary abnormality. Transvaginal ultrasound revealed a hypoechoic solid mass in the left ovary suggestive of a solid ovarian tumour. Hysterectomy and bilateral salpingo-oophorectomy were performed following which testosterone concentration returned to normal. Immunocytochemistry provided evidence of renin synthesis. This is a case of an unusual steroid cell tumour that caused virilisation accompanied by symptoms of secondary polycythaemia presumably as a result of erythropoietin production. This is the second case of a steroid cell tumour with an erythropoietic effect and the first that shows evidence of renin synthesis.

We present a case of anaemia and intestinal obstruction in a 78-year-old woman taking nonsteroidal anti-inflammatory drugs who was found to have diaphragm disease at laparotomy.

Objective: Cardiac transplant recipients often develop hypertension as a side effect of immunosuppressive treatment. The aim of this study was to use the serial endomyocardial biopsies taken to monitor rejection to study the early and sequential arterial changes in human myocardial resistance arteries as hypertension develops., Methods: At least 14 biopsies were studied from each of 23 patients, divided into a normotensive group (12 patients with a diastolic pressure never greater than 90 mm Hg) and a hypertensive group (11 patients with more than 10% of diastolic pressure measurements above 100 mm Hg). Morphometric analysis of between 30 and 50 arteries and arterioles in two widely separated histological levels from each biopsy was undertaken using an Optomax image analyser., Results: There was a correlation between blood pressure, particularly diastolic pressure, and rate of medial thickening of intramyocardial coronary resistance arteries and arterioles (P = 0.0025). There was also a correlation between serum cyclosporin A concentrations and mean artery wall thickness (P = 0.003)., Conclusions: Hypertension and cyclosporin A treatment are associated with significant wall thickening of intramyocardial resistance vessels in cardiac allograft recipients. These changes may be functionally and clinically important.

Arteries are usually studied morphometrically after pressurized fixation and resin embedding. These procedures are impracticable when dealing with diagnostic biopsies. The accuracy of arterial morphometry is determined partly by the degree of tissue distortion during section preparation. The axial ratios of 7340 arteries were measured in 353 endomyocardial biopsies from 23 patients and then compared with those expected from mathematical modelling. An excess of elliptical arteries was found. The distribution of orientation of the long axes of these best fitted a simulated 10 per cent linear distortion in the direction of microtomy. In conclusion, these results suggest that although there is some tissue distortion during sectioning, useful data may be obtained from morphometry of arteries in routinely processed endomyocardial biopsies.

A novel abnormality of intramural coronary arteries has been recently described in allograft cardiac biopsies. Three-dimensional (3-D) models of these abnormal arteries have now been constructed from serial histological sections of diagnostic post-transplant endomyocardial biopsies. These revealed that there was an interlacing meshwork of longitudinal smooth muscle bundles in abnormal arteries. In addition, the lumen and external surface of these arteries were irregular. This contrasted with reconstructions of normal control arteries in the same sections, which were smooth and straight. This elucidation of an unusual abnormality suggests that 3-D reconstruction of arteries in forceps biopsies may be a useful technique.

Most patients with nephroblastoma have high levels of plasma renin and some are hypertensive. Blood pressure falls after removal of the affected kidney, suggesting that nephroblastoma is associated with renin production either by the tumour or by the kidney. In this study, direct evidence was sought of renin gene expression in nephroblastoma using in situ hybridization. Digoxigenin-labelled riboprobes and an immunoperoxidase technique were used to detect cells containing renin mRNA: this showed renin gene expression in 9 out of 12 cases. There were positive cells within metanephric blastema and in occasional neoplastic glomeruloid structures, confirming that in seven cases nephroblastoma tumour cells expressed the renin gene. However, renin gene expression was also demonstrated in perivascular cells of uncertain lineage in seven cases; in five cases there was evidence of renin gene expression in both tumour cells and perivascular cells. The latter finding raises the possibility that some of the cells expressing the renin gene could be stromal cells. It is concluded that nephroblastomas contain cells that express the renin gene and that some are tumour cells, while other perivascular cells may be stromal cells.

Glomerular tufts were removed and scanning electron microscopy was used to study the interior of Bowman's capsule, in order to identify atubular glomeruli. Normal renal cortex was studied from six kidneys removed for tumour and six renal transplants removed for end-stage rejection. Atubular glomeruli occurred in normal renal cortex in less than 1 percent of glomeruli, but were more common in transplant nephropathy, representing up to 61 percent of glomeruli. Glomerular cysts were identified which also lacked a tubular connection. Both atubular glomeruli and glomerular cysts contained a contracted glomerular capillary tuft and in both, Bowman's capsule was lined mostly by parietal podocytes. It is suggested that atubular glomeruli may be precursors of the glomerular cysts. The glomerular tuft may produce filtrate which exits the glomerulus via the parietal podocytes on Bowman's capsule. In normal human kidney, the formation of atubular glomeruli by disconnection from the tubule may represent an alternative pathway for the gradual nephron loss that is associated with ageing. This process may be amplified in disease: disconnection from the tubule may be an important part of irreversible nephron damage in chronic allograft nephropathy.

Adrenal cytogenesis was investigated in response to 1) subcutaneous infusions of angiotensin (ANG) II (200 ng.kg-1.min-1); 2) high and low sodium intake; and 3) captopril treatment (10 mg.kg-1.day-1). Cell proliferation was assessed as uptake of 5-bromo-2'-deoxyuridine (BrdUrd) into nuclei. BrdUrd, infused continuously throughout 2 wk of treatment, was detected immunocytochemically. ANG II and sodium restriction caused hypertrophy of the zona glomerulosa with two- to threefold increases in BrdUrd indexes. After captopril, the glomerulosa appeared atrophied with pyknotic nuclei, but the BrdUrd index was unchanged. Zonae intermedia and fasciculata were unaffected by any treatment. Zona reticularis epithelial cells proliferated in response to ANG II and sodium restriction but were unaffected by captopril. In the medulla, captopril increased BrdUrd uptake, whereas ANG II, but not low sodium, caused a decrease. In conclusion, 1) proliferation of the glomerulosa and reticularis cells is specifically controlled by ANG II, 2) captopril may cause glomerulosa cells to die, and 3) blood pressure may control proliferation of the medulla.

We describe distinctive arterial lesions in endomyocardial biopsies from patients with human cardiac allografts. The lesions affected principally the media of small arteries and consisted of misorientation of smooth muscle cells and fibrosis. This remodelling was most prevalent in the subadventitial zone, but sometimes extended to involve the full thickness of the media. In the most extreme cases medial smooth muscle cells ran parallel to the long axis of the vessel and were segregated into small bundles and single cells separated by collagen which merged with the adventitial fibrosis. The intima was always normal. Abnormal arteries were present in 16% of 603 consecutive biopsies from 44 patients, and 39% of lesions occurred in 16% of patients. No lesions were found in endomyocardial biopsies from 25 non-transplanted patients, nor in mucosal biopsies from both transplanted and non-transplanted patients, confirming that the appearances were not due to biopsy artefact. There was early arterial remodelling in biopsies within two weeks of transplantation and none of the stages resembled vascular rejection. Fifty per cent of biopsies from some patients contained arterial lesions, suggesting that in susceptible patients they are common.

This study was conducted to define progression of atherosclerosis in both homozygous and heterozygous Watanabe heritable hyperlipidemic (WHHL) rabbits and to investigate the ability of the HMG CoA reductase inhibitor simvastatin to attenuate progression of the disease. We examined contractile responses to phenylephrine and endothelium-dependent relaxation in response to carbachol in thoracic aorta at 3, 6, 9, and 12 months in control New Zealand White (NZW) rabbits, homozygous WHHL rabbits, and heterozygous WHHL rabbits. Homozygous and heterozygous rabbits were treated with simvastatin (10 mg/kg per day) from 3 to 6 months and from 9 to 12 months of age. Simvastatin significantly reduced serum cholesterol levels in young heterozygotes, with a nonsignificant trend toward a reduction in older heterozygotes. In homozygotes, no significant fall was observed. Contractile function declined progressively with age in all groups--most in homozygotes and least in NZW rabbits. Relaxation was unaffected by age in NZW rabbits; relaxation declined in the heterozygotes and declined to a greater extent in homozygotes. Simvastatin retarded the loss of function in the young heterozygotes. Similar trends were observed in young homozygotes and older heterozygotes, with no effect in older homozygotes. Histological studies revealed the progressive development of early atherosclerosis in heterozygotes, and more advanced atherosclerosis was observed in homozygotes. Simvastatin did not inhibit development of atheroma. A correlation was observed between vascular function and structure. However, functional changes preceded the development of atheroma. In addition, we have demonstrated that simvastatin can help to reduce the loss of vascular function associated with the progression of atherosclerosis in the heterozygous WHHL rabbit.

The media of most blood vessels is occupied by vascular smooth muscle cells. In areas they may be replaced by glomus cells, pericytes or renin-secreting myoepithelioid cells. These cells may be regarded as phenotypic variants of vascular smooth muscle cells. In disease, ordinary vascular smooth muscle cells may also assume a spectrum of phenotypes ranging from contractile to largely secretory types. Therefore, the phenotype of smooth muscle cells that is involved in a disease process such as hypertension or one of its complications is likely to affect the structural outcome in blood vessels.

The control of zonation in the adrenal cortex has been studied by measuring DNA synthesis using an analogue of thymidine, bromodeoxyuridine (BrDUrd). Groups of rats were infused with BrDUrd for 10-14 days whilst being treated with: high or low sodium diets; captopril; angiotensin II; dexamethasone; an inhibitor of nitric oxide synthesis, L-NAME. DNA synthesis in the zona glomerulosa was increased by low sodium food and angiotensin and was decreased by dexamethasone, captopril L-NAME and a high sodium diet. Dexamethasone, not manipulations of the renin-angiotensin system, affected DNA synthesis in the outer zona fasciculata. The BrDUrd index in the zona intermedia was unaffected by any of the treatments and was generally lower than in adjacent zona fasciculata and zona glomerulosa cells. Cells of the zona reticularis appeared to be regulated independent of the zona fasciculata. BrDUrd uptake in nuclei of the adrenal medulla was inversely related to blood pressure. We conclude that DNA synthesis in each adrenocortical zone is independently controlled. Migration of cells within zones after proliferation is likely.

The peripolar cell is a glomerular epithelial cell situated within Bowman's capsule at its vascular pole. It is believed to be a secretory cell which forms part of the juxtaglomerular apparatus. Scanning electron microscopy was used to perform a comparative study of the morphology and number of peripolar cells in twelve mammalian species. The number of renin-secreting cells in kidney sections stained by renin antibodies and immunocytochemistry was counted. There was a marked inter-species variation in the number, size and appearance of peripolar cells. They were largest and most abundant in sheep and goat and fewest in dog, cow and human. There was no correlation between the numbers of peripolar cells and renin-secreting cells. This does not support the view that the peripolar cell is part of the juxtaglomerular apparatus.

We have recently documented the presence of podocytes lining part of Bowman's capsule at the vascular pole, in adult human kidney. In this study, we describe the deposition of immune complexes in Bowman's capsule in association with these parietal podocytes. We examined 1 year's consecutive human renal biopsies (n = 170). Transmission electron microscopy (TEM) revealed 18 cases in which parietal podocytes were present. Of these 18, there were 11 cases of glomerulonephritis, in which immune complexes were demonstrated in the capillary tuft by both TEM and direct immunofluorescence microscopy. In seven of these 11 cases, TEM showed immune complex-type deposits in Bowman's capsule, always associated with parietal podocytes. These deposits were similar in size, appearance, and distribution to the deposits in the capillary tuft. By contrast, non-specific electron densities within Bowman's capsule were found beneath both squamous parietal cells and parietal podocytes. In four cases, Bowman's capsule also showed focal positive immunostaining for complement components and/or fibrinogen. Both parietal and visceral podocytes showed similar fusion of pedicles. We suggest that filtration through parietal podocytes may be responsible for immune complex deposition and subsequent damage to the vascular pole of the glomerulus in human renal disease.

We have established optimal culture conditions for growing well-differentiated atrial myocytes from newborn rats. These myocytes show the morphological features of myocytes in intact atria; including perinuclear endocrine storage granules, contractile apparatus and numerous mitochondria. The cells synthesise, store and secrete immunoreactive ANP. Stored ANP is of similar molecular weight to pro-ANP (1-126); secreted ANP is the active form ANP (99-126) but processing appears to take place slowly after secretion. ANP secretion is stimulated by endothelin. Synthesis and secretion of ANP are markedly reduced by the beta-adrenergic agonist isoproterenol, and by forskolin.

There is evidence to suggest that the human placenta may synthesize atrial natriuretic hormone (ANH). To test this hypothesis we examined specimens of normal term placenta obtained at elective caesarean section for evidence of either storage or synthesis of this peptide. No immunocytochemical or ultrastructural evidence of ANH storage was found. RNA extracted from cultured cytotrophoblast cells, the chorionic or decidual plates, or from placental villi contained no ANH-encoding messenger RNA by Northern blot analysis. Polymerase chain reaction amplification of these RNA extracts using primers directed to the midportion of the ANH gene failed to demonstrate any evidence of ANH-encoding RNA. We conclude that ANH is neither stored nor synthesized within the normal term placenta, and thus a purely endocrine role for this peptide within the fetoplacental compartment is proposed.

Advanced glycosylation endproducts (AGE) are intraprotein crosslinks which form in the late stages of the Maillard (browning) reaction. It is unknown whether local changes in AGE-modified collagen occur within arteries. We measured AGE-modified collagen as collagen-linked fluorescence (CLF) in human arterial tissue and in various forms of atherosclerotic plaque. All tissues showed single fluorescence peak at excitation wavelength 340 nm and emission wavelength 420-440 nm. CLF in the aorta was 27.9 +/- 8.5 units/mg, in the coronary arteries 25.9 +/- 6.3 units/mg and in the tendon 47.8 +/- 11.5 units/mg. CLF in the skin correlated with CLF in the aorta (r = 0.467, P = 0.025) but not with CLF in coronary arteries (P = 0.935). In areas of aorta covered by superficial plaque, CLF was decreased compared with adjacent, atheroma-free segments (22.2 +/- 5.2 units/mg vs. 27.9 +/- 8.5 units/mg; P = 0.01). The CLF of collagenous plaques correlated with CLF of the atheroma-free regions. Individuals with low to moderate atheroma had lower (20.0 units/mg) CLF in superficial atherosclerotic plaques than patients with severe atheroma (22.5 units/mg; P = 0.0466). Our results indicate that local changes in vascular AGE-collagen concentration occur in atherosclerosis. This finding may have pathogenetic significance in atherosclerosis.

Atrial and ventricular myocytes from fetal and newborn rats were cultured in medium supplemented with fetal or newborn calf serum with and without glucocorticoid. Myocyte morphology was examined by light and electron microscopy, and the amount of stored and secreted atrial natriuretic peptide (ANP) was measured. Without dexamethasone, neonatal atrial myocytes cultured for 7 days contained myofibrils organized into sarcomeres and numerous endocrine granules containing immunostainable ANP. Secretion of immunoreactive ANP reached a peak between days 7 and 9 of culture. Myocytes from fetal rats secreted ANP but contained few endocrine granules, and myofilaments were poorly organized. By contrast, the addition of dexamethasone (1 nM-1 microM) to the culture medium of newborn myocytes promoted development of numerous endocrine storage granules, mitochondria, and myofibrils with prominent Z-bands. Dexamethasone also increased the cellular content of ANP and ANP-specific mRNA in both atrial and ventricular myocytes. In the presence of dexamethasone myocytes maintained their structural integrity for periods of at least 45 days.

Objective: To characterize the pattern of renin containing cells (RCC) within the human kidney between 20 weeks of gestation and 6 months of postnatal life., Design: Descriptive study using paraffin-embedded blocks of kidney stored following postmortem examination., Methods: Sections of kidney were stained immunocytochemically using an antibody to human renin; the proportion of RCC within each of three zones (superficial, middle and deep) of the cortex, and their anatomical relation to individual glomeruli were determined. The cases were divided into five groups for analysis to gestational or postnatal age., Results: Fetal RCC were usually at the vascular pole of the most mature glomeruli within the deeper areas of the cortex and were occasionally located within glomeruli. This distribution persisted until birth, even when the kidney was histologically mature. By contrast there were fewer RCC in neonatal and infant kidneys and, as in adult kidneys, these were located predominantly in the superficial cortex., Conclusion: The change in RCC distribution around the time of normal birth may relate to the transition to independent renal function. The location and density of RCC during fetal life may influence renal perfusion and amniotic fluid production.

The peripolar cell is a recently described glomerular epithelial cell which is situated within Bowman's capsule at the vascular pole. It contains cytoplasmic granules which contain plasma proteins, although it may also have a secretory function. The relationship between peripolar cells, other granulated glomerular epithelial cells and tubular epithelial cells is unclear. We have studied 242 biopsies from 19 types of renal disease for peripolar cells, other granulated epithelial cells and granulated tubular epithelial cells. Peripolar cells were most numerous in mesangioproliferative glomerulonephritis, IgA nephropathy, focal segmental glomerulosclerosis, membranous glomerulonephritis and lupus nephropathy. Other granulated glomerular epithelial cells were most prominent in diffuse lupus nephropathy, focal glomerulonephritis, acute vascular transplant rejection, crescentic glomerulonephritis and mesangioproliferative glomerulonephritis. Granulation of the tubular epithelium was most prominent in minimal change nephrotic syndrome and amyloidosis. It is likely that the granules in tubular epithelial cells represent lysosomes containing plasma proteins which have been absorbed from the tubular fluid. However, granulation of glomerular cells may represent a more specific response to glomerular damage. In addition, peripolar cells are prominent in only certain diseases, suggesting a specialized function.

The peripolar cell is a unique cell type in the mammalian glomerulus. Peripolar cells are said to be identifiable during light microscopy by their cytoplasmic granules and by their position at the vascular pole; and during scanning electron microscopy by their distinctive surface morphology. We used both techniques to count peripolar cells in 6 normal rat kidneys. Scanning microscopy revealed that 55(+/- 5)% of glomeruli contained at least one peripolar cell whereas light microscopy revealed granulated peripolar cells in only 4(+/- 2)% of glomeruli. Vascular poles which contained peripolar cells previously identified by scanning were then examined by light and by transmission electron microscopy. Serial sections through these peripolar cells demonstrated the absence of cytoplasmic granules. Our observations suggest that the majority of peripolar cells in the rat contain no granules.

We have examined 12 autopsy kidneys from cases of malignant hypertension and compared them with normal controls. Peripolar cells and other granulated glomerular epithelial cells were counted in serial paraffin sections, and renin-containing cells were quantified using an immunoperoxidase technique and a human renin antiserum. There were significantly more peripolar cells and other granulated glomerular epithelial cells in the cases of malignant hypertension. Most granulated glomerular epithelial cells were podocytes, situated at the periphery of the tuft. Peripolar cells correlated in number with other granulated glomerular epithelial cells and they had a similar distribution within the renal cortex, but there was no correlation between either of these cells and the number of renin-containing cells. There was hyperplasia of renin-containing cells in some juxtaglomerular apparatuses (JGAs), although the proportion of renin-positive JGAs was unaltered. These results suggest that peripolar cells and other glomerular epithelial cells react in a similar way in malignant hypertension, but they do not support the hypothesis that peripolar cells are part of the JGA.

The peripolar cell is a recently described glomerular epithelial cell which may be a new secretory component of the juxtaglomerular apparatus (JGA). The purposes of this study were to identify immunohistochemical markers specific for peripolar cells and to elucidate the composition of their cytoplasmic granules. We examined tissue from normal human and sheep kidneys with a variety of monoclonal antibodies and antisera. A minority of peripolar cells showed immunoreactivity for vimentin but no other intermediate filament. Neuroendocrine markers were negative. The granules of peripolar cells contain a variety of plasma proteins with the exception of IgM. It is likely that peripolar cells absorb plasma proteins from the glomerular filtrate. The reason for this is uncertain; however, their unique position at the vascular pole of normal kidneys suggests a specialized function.

A three-dimensional and morphological study of the human JGA was undertaken to establish a background for understanding the changes in this vital apparatus during various physiological and pathological conditions. Three-dimensional reconstruction was carried out using a computer program "GLOM". Serial sections of normal human kidneys were used after staining with specific human renin antiserum. Three-dimensional reconstruction revealed renin-positive cells in the afferent and efferent arterioles and interlobular arteries away from the JGA area. A close contact was demonstrated between renin-positive cells and the macula densa. The frequency of positively stained JGAs was significantly higher in the superficial glomeruli compared to the deep glomeruli. The high renin content of the superficial glomeruli suggests higher generation of angiotensin, which may contribute to the regulation of the GFR as proposed by other workers. This preliminary study on normal human JGA is to be extended to hypertensive and renal failure patients.

The glomerular peripolar cell may be a secretory component of the juxtaglomerular apparatus. To investigate this hypothesis we studied kidneys with the renin-angiotensin system activated by two different stimuli in order to compare the responses of peripolar cells and renin-secreting cells. We examined 10 human kidneys, removed for renal artery stenosis and 11 autopsy cases of Addison's disease with appropriate controls. We counted granulated peripolar cells in serial paraffin-embedded sections and renin-containing cells were quantified using an immunoperoxidase technique with an antiserum to human renin. There was a five-fold increase in the number of renin-containing cells in both renal artery stenosis and in untreated, but not in treated, Addison's disease. Peripolar cells were increased in number in three cases of renal artery stenosis, but were unaltered in both treated and untreated Addison's disease. Therefore, neither a reduction in renal perfusion pressure (renal artery stenosis), nor sodium depletion (Addison's disease) consistently affect peripolar cells in humans. These findings do not support the hypothesis that the peripolar cell is part of the juxtaglomerular apparatus.

There is now morphological evidence from several species that the peripolar cell is a distinctive glomerular cell which may have a secretory function, although a secretory product has not been identified. Peripolar cells, like other glomerular epithelial cells, probably absorb plasma proteins from the glomerular filtrate. Peripolar cells may participate in regulation of sodium balance and the changes in renal function which occur at the time of birth. They are ideally situated to monitor the composition of the glomerular filtrate and/or the calibre of the glomerular arterioles. The relationship between peripolar cells and other granulated glomerular epithelial cells must be clarified, however their morphology and unique anatomical site is suggestive of a specialised function.

We report an association between renal artery stenosis and papillary necrosis. We studied three kidneys with renal artery stenosis, two of which showed ipsilateral acute papillary necrosis. In all three cases there had been a sudden fall in perfusion of the ischaemic kidney. In the case with intact papillae, immunostainable renin was normal in amount and distribution, whereas both kidneys with papillary necrosis showed hyperplasia of renin-containing cells, and these were mainly in the JGAs of the juxtamedullary cortex. Since the contralateral kidneys were spared, we suggest that in an ischaemic kidney with hyperplasia of renin-secreting cells in the deep cortex, local activation of the renin-angiotensin system could cause acute papillary necrosis due to vasoconstriction.

A prospective study of four children with nephroblastoma has demonstrated elevation of plasma inactive renin levels at the time of detection of recurrent disease. Three of the four children had been shown to have elevated inactive renin levels at their initial presentation with primary nephroblastoma. These levels returned to normal following operation and chemotherapy. The observation provides further evidence that plasma inactive renin may be a useful tumour marker for nephroblastoma.

Hypertension complicates chronic pyelonephritis. Since arterial narrowing is common in the damaged kidney, activation of the renin-angiotensin system due to renal ischaemia has been suggested as a pathogenetic mechanism. We used an antiserum to human renin and an immunoperoxidase technique to study the anatomy of renin-containing cells (RCC) in 18 kidneys removed for pyeloneophritis. We independently assessed the degree of arterial narrowing and correlated these variables with the clinical findings. There was histological evidence of hyperplasia of RCC in 5 of the 6 hypertensive patients and in 7 of the 12 non-hypertensive cases. There was no difference in the apparent number or distribution of RCC between the hypertensive and the non-hypertensive cases. Also, the degree of arterial narrowing did not correlate with either the hyperplasia of RCC or the blood pressure of the patients. Our results do not support the hypothesis that narrowing of the intrarenal arteries is important in the pathogenesis of hypertension in pyelonephritis. In our cases, the renal veins were more severely damaged than the arteries and their lumina were often obliterated by organized thrombus. We suggest that such widespread obliteration of the renal venous tree could impair blood flow and contribute to the tissue damage in the pyelonephritic kidney.

An infant with severe hypertension who had a nephroblastoma which was secreting active renin is described. Nephroblastoma must be included in the differential diagnosis of hypertension associated with increased renin concentrations, even in the absence of an abdominal mass.

Spontaneously hypertensive rats (SHR) are used to study the pathogenesis of essential hypertension. This study investigates the role of the renin-angiotensin system (RAS) in the pathogenesis of hypertension in SHRs and the morphometry of the JGA by a three-dimensional computer reconstruction program "GLOM" and electron microscopy. Systolic blood pressure (SBP) (tail cuff method) was higher in SHRs compared to controls (P less than 0.001). Plasma renin concentration (PRC) was lower in SHRs than in controls (P less than 0.001). Reconstruction of the JGA revealed granulated JG cells in the afferent and efferent arterioles and in the vascular tree away from the JGA area. Electron microscopy showed granulated JG cells in the afferent and efferent arterioles. The percentage volume of the granulated JG cells in SHR was significantly higher than in controls (P less than 0.01). A relationship was found between the percentage volume of granulated JG cells and the SBP in SHRs (r = 0.933, P less than 0.05). The wall/lumen perimeter ratio was also significantly higher in the SHRs compared to the controls (P less than 0.05). Low PRC in SHRs has been reported by several workers. The apparent hyperactivity of the JGA may indicate failure of renin release or an abnormal synthesis/secretion rate.

Renal biopsies were examined from 17 renal transplant recipients before and after conversion from cyclosporin to azathioprine, and in 17 patients who remained on cyclosporin. All patients had stable renal function. We used an immunoperoxidase technique with an antiserum to human renin to identify renin-containing cells. We demonstrated hyperplasia of renin-containing cells in patients treated with cyclosporin. Numbers of renin-containing cells decreased after conversion to azathioprine. We suggest that local activation of the intrarenal renin-angiotensin system could mediate the effects of cyclosporin on renal haemodynamics. This could play a role in the pathogenesis of cyclosporin nephrotoxicity and cyclosporin hypertension.

Most cases of nephroblastoma have high plasma levels of prorenin which is biologically inactive. Plasma prorenin levels fall to normal following nephrectomy. In order to ascertain whether renin synthesis occurs in nephroblastomas we decided to search for renin-specific mRNA using a cDNA probe and Northern blot analyses on total RNA purified from snap-frozen human tumour tissue obtained at nephrectomy. We demonstrated renin-specific mRNA in 5/11 (45 per cent) nephroblastomas. It was 1.6 Kb in length, similar to the mRNA detected in normal kidney tissue and in kidneys with renal artery stenosis. In one of the cases of nephroblastoma, in which we could detect no normal renin mRNA at 1.6 Kb, the cDNA probe hybridized with a higher molecular weight mRNA 3 Kb in length. We conclude that some nephroblastomas synthesize renin.

In 10 kidneys removed for hypertension due to renal artery stenosis, the histological appearances varied from negligible ischaemic damage to end-stage ischaemic atrophy. We stained the renin-containing cells in tissue sections using an antiserum to pure human renin and an immunoperoxidase technique. In all kidneys there was hyperplasia of the renin-containing cells both in juxtaglomerular apparatuses (JGAs) and in arteries outside the JGA, where these cells extended proximally as far as the interlobular arteries. We mapped the distribution of renin-containing cells and found them in all zones of the renal cortex; in three kidneys they were predominantly in the superficial cortex; in four they were distributed more evenly throughout the width of the cortex; but in three kidneys the normal gradient was reversed, with most of the cells being in the juxtamedullary cortex and, in two of the cases, little or no stainable renin in the superficial cortical JGAs. We suggest that these abnormalities in the distribution of renin-containing cells could affect both the pattern of intrarenal blood flow and the site in the kidney at which secreted renin enters the blood.

We studied kidney sections from 15 cases of polyarteritis using an immunocytochemical technique to demonstrate cells containing immunoreactive renin. Ten cases of classical polyarteritis nodosa showed hyperplasia of renin-containing cells in areas of renal cortex with histological evidence of ischaemia--appearances indistinguishable from those seen in renal artery stenosis. Histologically normal cortex showed little or no immunostainable renin. In the ischaemic areas there was loss of the normal gradient of renin-containing cells from superficial to deep cortex. In many cases this gradient was abolished or even reversed; in some cases most renin-containing cells were in juxtaglomerular apparatuses. This alteration in the distribution of immunoreactive renin has only been described in renal artery stenosis in man. In five cases of microscopic polyarteritis there were fewer than normal numbers of renin-containing cells. We suggest that in classical polyarteritis nodosa, focal ischaemia causes activation of the renin-angiotensin system analogous to the changes caused by renal artery stenosis. This may be important in the pathogenesis of hypertension in this condition. By contrast, in microscopic polyarteritis, the appearances of the juxtaglomerular apparatus and the reduced amounts of immunostainable renin suggest suppression of renin synthesis.

We used scanning electron microscopy to study the glomerular peripolar cell in the kidneys of seven sheep. Peripolar cells were present in a variable proportion (3.6-100%) of glomeruli. Although on average two peripolar cells were present at each vascular pole, up to ten were seen on occasion. They were more often related to the afferent than to the efferent arteriole. Mapping the relative position of each cell failed to reveal any zonal distribution in the renal cortex. Scanning electron microscopy showed that they were globular in shape and had a bossellated surface. We showed by examination of cells which had been broken open that this appearance was due to the presence of cytoplasmic granules that produced bulging of the cell membrane. We suggest that scanning electron microscopy is a suitable method for studying this cell in the mammalian kidney.

We have previously shown impaired ventricular function in asymptomatic middle-aged type 1 (insulin-dependent) diabetic patients who had no evidence of coronary artery disease. The diabetic patients had normal coronary angiograms but reduced ventricular ejection fraction on exercise. To examine the possible contribution of small vessel disease to this functional abnormality, we compared endomyocardial biopsies from seven symptom-free type 1 diabetic patients with biopsies from seven age- and sex-matched non-diabetic subjects. Interstitial fibrosis was present in three diabetic patients, arteriolar hyalinization in three patients and arteriolar thickening was observed in five patients. Morphometry performed on electron micrographs showed no significant difference in the thickness of the capillary basal lamina between diabetics and controls. While the functional significance of the abnormalities on light microscopy is unclear, our findings indicate that the abnormality of cardiac function described in diabetes is not associated with thickening of the myocardial capillary basal lamina.

This is a case report of a 14-year-old girl who presented with malignant hypertension. She had high plasma levels of both active and inactive renin and investigation revealed a renal tumour. The tumour, a renal cell carcinoma, was removed by nephrectomy following which the blood pressure and the plasma renin levels fell to normal. An immunocytochemical study using an antibody to pure human renin showed no detectable renin in the kidney but the tumour contained a population of granular cells which showed strong positive staining for immunoreactive renin. We present the clinical, biochemical, histological, immunocytochemical and ultrastructural features of this case as evidence that this was a renin-secreting renal cell carcinoma.

Renin-containing cells have been identified in nephroblastoma. A prospective study of eight children with nephroblastoma has demonstrated abnormally high levels of total renin. The increase in total renin was due to increased levels of inactive renin (prorenin), rather than the active renin. These high levels decreased to normal after operation. The plasma level of inactive renin could be a useful biochemical tumor marker in nephroblastoma.

This is a case report of a renal carcinoma which was secreting inactive renin. Using an antibody to human renin and the indirect immunoperoxidase technique, the renin-containing cells were localised within the tumour. These were found to be small granular cells situated in a perivascular position. The histological immunocytochemical and ultrastructural features of these cells are described.

A case of megacolon is described in which there was an unusual and focal hyperplasia of enterochromaffin cells in the mucosa. These formed discrete spherical acini in the lamina propria. These acini were not neoplastic and their significance is discussed.