Renin-containing Cells Research Articles

An immunohistochemical study on the embryonic development of renin-containing cells in the mouse and pig.

The prenatal occurrence and distribution of renin-containing (RC) cells were investigated immunohistochemically in mouse and pig embryos. The RC cells of the mouse embryo were first observed at the 13th day of gestation at the walls of the renal, the mesonephric, the adrenal, the abdominal arteries, the adrenal glands and the testis. As the gestation of the mouse progressed, the RC cells had a tendency to localize in areas of the vascular pole of the metanephric glomerulus. In pig, when CRL was 0.8-2.0 cm, RC cells first appeared at the ventral walls of the dorsal aorta, the omphalo-mesenteric (i.e., the cranial mesenteric), the mesonephric, the mesonephric afferent glomerular arteries/arterioles and the inside of the mesonephric glomerulus. As the length of the pig embryo increased, no renin-immunoreactivity could be demonstrated at the degenerated mesonephros, while in the metanephros marked immunoreactivities were found only at the terminal regions of intralobular arteries, i.e., afferent arterioles or the vascular pole of the glomerulus.

Renin in Glioblastoma Multiforme and Its Role in Neovascularization

Significant proliferation of capillaries with hyperplastic vascular endothelium is one of the characteristic histologic features of glioblastoma multiforme (GBM). It has been shown that the renin-angiotensin II cascade stimulates new vessel formation. The presence of renin in several types of highly vascularized neoplasm suggests that it may also be implicated in the mechanism of tumor angiogenesis. In order to study the possible relationship of renin to GBM, immunohistochemical search for human renin was carried out in ten instances of such a tumor. Eight of these cases demonstrated renin-containing neoplastic astrocytes, whereas seven cases of reactive gliosis and six cases of low-grade astrocytoma revealed no renin-containing cells. The immunostaining was not present after preabsorption of the renin antiserum with pure human renin or substitution of preimmune serum for the specific renin antiserum. Because it has also been demonstrated that a product of renin, angiotensin II, has angiogenic properties, it seems reasonable to postulate that renin, through angiotensin II, may play a role in the mechanism of GBM-associated neovascularization.

The anatomy of the renin-secreting cell in adult polycystic kidney disease

We used a human renin antiserum and an immunoperoxidase method to investigate the distribution of renin-containing cells in 19 adult polycystic kidneys: 9 autopsy and 10 nephrectomy cases. These cells were present in residual normal kidney, in scarred renal parenchyma and in area of fibrous tissue. They were situated mainly in juxtaglomerular apparatuses (JGAs) and in the walls of arteries and arterioles. A semi-quantitative analysis showed hyperplasia of JGA renin-containing cells in the untreated autopsy cases. In both groups there was an abnormal distribution of renin-containing cells; only 50% were located in the JGAs the remainder were mainly in the walls of small arteries. These were often thin, attenuated vessels in the walls of cysts. Cells containing renin were also found isolated in fibrous tissue separate from the arterial tree. This abnormal location of the renin-containing cells suggests that they may respond to different stimuli than those in normal kidneys, and their abnormal distribution could affect both the intrarenal action of renin and also its release into the blood.

Inactive Renin: A Tumor Marker in Nephroblastoma

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.

Distribution and morphology of the renin-containing cells in the amphibian kidneys.

Studies on the components of the juxtaglomerular apparatus (JGA), the ultrastructural characteristics of juxtaglomerular (JG) cells and the distribution of renin-containing (RC) cells in three species of amphibians were performed in the kidneys by histological, immunohistochemical and electron microscopical methods. The JGA consisted of afferent and efferent glomerular arterioles and JG cells, and there was no extraglomerular mesangium. The macula densa-like structures were observed only in Rana species. RC cells were localized scarcely in a wide range in the walls of afferent vessels, but were not detected in the walls of efferent vessels. In Xenopus species, RC cells were demonstrated numerously in the intraglomerular region. Ultrastructurally, the secretory granules occasionally showed fusiformic structures (containing conglomerated granules). A large number of non-myelinated nerve fibers containing numerous small vesicles and some large dense cored vesicles were observed in the tunica adventitia, and they invaded partly into the concave regions of JG cells. These results suggests that the amphibian JGA is phylogenetically located in an intermediate position between that of fishes and mammals.

Intrarenal generation of angiotensin II evaluated by an electrophysiological technique.

Angiotensin II (ANG II) reversibly depolarizes renin-containing juxtaglomerular epithelioid cells (JGECs) of the hydronephrotic mouse kidney afferent arteriole. This depolarizing response was utilized to assess changes in ANG II concentration in the vicinity of JGECs in order to test whether ANG II is generated from ANG I and artificial renin substrate (ARS) in this preparation. Depolarizations were also produced by the application of ANG I and ARS in the superfusing medium. These responses to ANG I and ARS were completely blocked by saralasin. Hence, our findings are indicative for an intrarenal, local generation of ANG II. As opposed to saralasin, several converting enzyme and renin inhibitors only diminished but generally did not abolish the actions of ANG I and ARS, respectively. These results suggest an alternative, nonrenin and non-converting enzyme-dependent pathway of ANG II generation in renal tissue.

Inactive renin: A tumor marker in nephroblastoma

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.

Junctional transmission in renin-containing and smooth muscle cells of the afferent arteriole.

Intracellular recordings were done in renin-containing juxtaglomerular (JG) and vascular smooth muscle (VSM) cells of the mouse kidney afferent arteriole. Both cell types exhibited a membrane potential around -75 mV and spontaneous depolarizing transients resembling spontaneous excitatory junction potentials (SEJPs) in the arterioles of other organs. The amplitude distribution of these randomly occurring transients was skewed in both cell types with a modal value of 1.2-1.9 mV. Activation of presumably postjunctional alpha 1-, P2-, ANG II- and AVP-receptors depolarized JG and VSM cells. Application of the P1-purinoceptor agonist 2-chloroadenosine strongly increased frequency and amplitude of the SEJP-like events, whereas these transients were abolished by the P1-purinoceptor antagonist 8-phenyltheophylline, both substances presumably acting on prejunctional receptors. The SEJP-like events were completely depressed by reserpine treatment, but not abolished by alpha 1-, alpha 2-, and P2-antagonists. At present, it cannot be decided, whether norepinephrine is the sole transmitter in the afferent arteriole, acting on specialized junctional adrenoceptors with the P2-purinoceptors being irrelevant for junctional transmission, or whether both substances are co-transmitters. Except norepinephrine and ATP, all other transmitter candidates tested were ruled out for various reasons.

Anatomy of the renin‐angiotensin system in the normal and pathological kidney

In this review we describe the contributions made by immunocytochemistry to our knowledge of the renin-angiotensin system in the normal and the pathological kidney. Most of the renin-secreting cells appear to be on the outer aspect of the vessel wall, supporting the view that renin is secreted mainly into the interstitium of the kidney rather than into the lumen of the vessel. Angiotensin II immunoreactivity is present within renin-secreting cells. The angiotensin II appears to be present in high concentration in the renin storage granules and is therefore presumably secreted from the cell with renin. The pathways by which renin is secreted from the cell have also been clarified. In pathological kidneys, the reactions of renin-secreting cells to variation in functional demand have been confirmed. Renin-containing cells have also been found in most types of renal tumours and occasional cases probably secrete renin or prorenin into the blood. In renal tumours and in the developing kidney (in all species studied) the renin-containing cells are also intimately associated with blood vessels.

Hyperplasia of renin-containing cells in a malignant pheochromocytoma: An immunohistochemical and semiquantitative study

The renin-containing cells in the kidneys of a patient with malignant pheochromocytoma were investigated immunohistochemically. Elevated plasma renin and catecholamine levels were detected during the clinical course. Remarkable hyperplasia of renin-containing cells was observed in the afferent arterioles and interlobular arteries. Semiquantitative assessment was performed to compare this case with cases of renovascular hypertension, with one case of malignant nephrosclerosis, and with six cases without hypertension. The grade of hyperplasia of renin-containing cells in pheochromocytoma was similar to that in renovascular hypertension and was different from that observed in control cases. Histologic examination of the kidneys revealed neither stenosis of the renal arteries nor ischemic changes of glomeruli. Direct stimulation of renin-containing cells by catecholamines is suggested as the cause of the hyperplasia. This is the first morphologic demonstration of hyperplasia of renin-containing cells in pheochromocytoma.

Renin status of the afferent arteriole and ultrastructure of the juxtaglomerular apparatus in 'superficial' juxtamedullary nephrons from rats.

The present light (LM) and transmission electron microscopic (TEM) studies were carried out to further document the anatomy of the 'superficial' juxtamedullary nephrons (SJMNs) located on the inside cortical surface of the rat kidney. TEM revealed that SJMNs possess all vascular and tubular cell types constituting the juxtaglomerular apparatus (JGA) in typical cortical and juxtamedullary nephrons (JMNs). Proximal to the glomeruli, epithelioid cells filled with secretory granules predominated in the media of afferent arterioles. The presence of renin in the granules was immunocytochemically demonstrated by the protein A-gold method. Further upstream from the glomeruli, epithelioid cells alternated with plain smooth muscle cells. The use of renin and angiotensin II antisera revealed similar arteriolar distributions of renin and angiotensin II positive cells in SJMNs as well as in typical JMNs. Numerous nerve terminals were found along afferent and efferent arterioles, suggesting a dense innervation of these vessels. The distribution of renin-containing (i.e., epithelioid) cells in the preglomerular arterioles was assessed in various nephron populations by LM using the PAP method and renin antiserum. In SJMNs, most renin-positive cells were found in the vicinity of the JGA along a mean arteriolar length of 35 +/- 3 micron (range 7-107 micron). In JMNs, renin-positive cells had a similar distribution along a mean arteriolar length of 35 +/- 1 micron. Scattered renin-positive cells were observed up to a maximal arteriolar length of 173 and 238 micron in SJMNs and JMNs, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

The granular peripolar cell of the human glomerulus: a new component of the juxtaglomerular apparatus?

Using serial sections of resin-embedded tissue we found granular peripolar cells in six human kidneys. They were present in 3% to 28% of the glomeruli. Using an immunoperoxidase staining technique and an antibody to pure human renin we showed that the human peripolar cell contains no immunostainable renin. The number of peripolar cells correlated with the number of juxtaglomerular apparatus (JGAs) with renin-containing cells; their distribution within the renal cortex was similar, both being found predominantly in glomeruli in the superficial cortex. There was a close anatomical relationship between the peripolar cells and the renin containing cells in individual JGAs. These findings suggest the possibility of a functional relationship between the peripolar cell and the other components of the juxtaglomerular apparatus.

Diminished number of renin-containing cells in kidney biopsy samples from hypertensive women immediately postpartum: An immunomorphologic study

Normal human pregnancy is characterized by increased angiotensinogen [I], plasma renin activity (PRA), plasma renin concentration (PRC), plasma angiotensin 11 levels, and plasma aldosterone levels [2—4]. In the hypertensive pregnant women, plasma angiotensin II levels are variously reported as being higher [51 or lower [4] than they are in normal pregnancy. In the late course of hypertensive pregnancies, PRA and PRC levels are relatively low [4, 61, although higher than those found in nonpregnant normotensive women. The cause for such findings in hypertensive pregnancies remains uncertain, and the role of the renin-producing system within the maternal kidney has not been directly investigated. Using a specific antirenin antiserum, we previously showed that in patients with various glomerular and vascular renal diseases, the number of renin-containing cells was increased when compared to normal kidney biopsy samples [71. We now extend our study to hypertensive pregnant women who have either preeclampsia or isolated high blood pressure (HBP) or previous renal disease. The study shows that, in comparison with nonpregnant normotensive women, all these patients have fewer renin-containing cells upon postpartum renal biopsy examination. Methods: Patients. Sixty renal needle biopsy samples from women presenting with HBP during their pregnancy were studied retrospectively. The samples were taken 6 to 8 days after delivery. HBP was defined as diastolic pressure 90 mm Hg. The patients were divided into three groups. Group 1. The preeclamptic group included 19 women (mean age, 25 years) presenting with HBP, proteinuria 1 g per day, and uricemia 340 moles/liter appearing during the last 3 months of pregnancy. Seven had the nephrotic syndrome at the time of biopsy. All but 3 women were primigravidae. Group 2. The group of isolated HBP ofpregnancy involved 29 patients (mean age, 28 years). Twenty-two of these patients had HBP that developed in the last trimester, five patients had HBP that appeared in the first 6 months of pregnancy, and two patients had recurrent HBP in the course of successive pregnancies. Of the 48 renal biopsy samples from these two groups, 34 displayed typical aspects of pregnancy-induced nephrop-

The renin-angiotensin system in nonmammalian vertebrates.

The most primitive components of the RAS appeared early in the phylogenetic history of vertebrate animals. It is probable that renin granules were present in the kidneys of ancestral chordates before divergence in the evolution of actinopterygian fish and tetrapods occurred. Granulated juxtaglomerular cells similar to the renin-containing cells of the mammalian nephron are found in most extant vertebrate species although not in agnathan and elasmobranch fish. A macula densa occurs in amphibians, birds and mammals; and an extraglomerular mesangium, only in birds and mammals. Renin-like activity and angiotensin-like pressor material have been demonstrated in all classes of vertebrates. The amino acid sequences of native ANG I have been determined for representative species of teleost fish, amphibian, reptile and bird. These peptides differ from mammalian angiotensins at positions 1, 5 and 9. The RAS appears to be involved in osmoregulation, ionoregulation and the control of blood circulation. Prolonged hypovolemic hypotension or sodium depletion increases renin levels. Angiotensins elicit drinking and stimulate transepithelial ion transport. However, direct steroidogenic and antidiuretic hormone-releasing activities, which would promote mineral and fluid conservation, have not been demonstrated unambiguously in nonmammalian vertebrates. ANG II raises blood pressure by direct vasoconstrictor action on arteriolar muscles in some animals, but perhaps more generally by acting on the nervous system and adrenal paraneurons. In birds the hormone also has a hypotensive effect. ANG II stimulates the SNS in agnathans, elasmobranchs, teleosts, amphibians, reptiles, birds and mammals. Thus, modulation of sympathetic activity may be one of the most primitive and conservative functions of the RAS. For this reason, nonmammalian vertebrates are valuable models for studying the neurogenic actions of angiotensin II relevant to hypertensive disease.

Abnormalities of renin-containing cells in human glomerular and vascular renal diseases

The distribution of renin was investigated by immunofluorescence in human kidney biopsy specimens (27 patients with lipoid nephrosis, 39 with Berger disease, 17 with membranous glomerulonephritis, 5 with thrombotic microangiopathy, and 7 with malignant nephroangiosclerosis). A semiquantitative assessment was carried out. Two ratios were found significatively increased in the study groups as compared with the control group: JGA + and JGA ++ which expressed, respectively, the number of fluorescent JGA in relation to the number of glomerular sections and the number of fluorescent JGA with more than six renin-containing cells (RCC) in relation to the number of immunoreactive JGA. Highest values were observed in patients with thrombotic microangiopathy and malignant nephroangiosclerosis (P less than 0.001). The above immunomorphological parameters were correlated with clinical and laboratory data. A positive dependency was found between JGA + and JGA ++ ratios and a low sodium diet, diuretic therapy and serum creatinine. A negative dependency was seen in the albumin and hemoglobin serum levels. No correlation was found with blood pressure values. These observations suggested that decreased plasma volume and impaired renal function could be factors leading to an increased renin production in the kidney.

Immunohistochemical localization of renin in luteinizing hormone-producing cells of rat pituitary.

The location of renin (EC 3.4.99.19) in rat pituitary was determined by the peroxidase-antiperoxidase immunohistochemical technique. By using antisera prepared with purified rat renal renin, an immunoreactive substance was localized within ovoid cells scattered throughout the anterior pituitary. These cells were shown to be luteinizing hormone-producing cells by staining with anti-luteinizing hormone antisera in adjacent sections. By using the double staining method, the renin-containing cells were differentiated from cells containing corticotropin, thyrotropin, growth hormone (somatotropin), and prolactin (mammotropin). These results suggest a possible local role for renin in the anterior pituitary.

Immunocytochemical localization of renin in the submandibular gland of the mouse during postnatal development

The localization of renin in the developing mouse submandibular gland was studied immunocytochemically using the unlabelled antibody-enzyme method of Sternberger ('74). Bouin-fixed submandibular glands of mice of both sexes were examined at 5-day-intervals from birth (day 0) to 50 days of age. At all stages studied, only granular convoluted tubule (GCT) cells stained immunocytochemically for renin; such cells were first seen in glands of 30-day-old males and of 30-day-old females. The size and number of renin-containing GCT cells increased rapidly in males, attaining adult status by 50 days of age. In females, differentiation of GCT cells immunoreactive for renin was slower and less regular than in males, and at 50 days of age the GCT segment had not yet reached adult conditions with respect to the distribution of renin. Renin appears in GCT cells at later ages than other GCT cell products (e.g., EGF and amylase), suggesting the existence of independent developmental control for the expression of various biologically active substances in the GCTs.

Homogeneous cell populations from rabbit kidney cortex. Proximal, distal tubule, and renin-active cell isolated by free-flow electrophoresis.

A single-cell suspension has been prepared from rabbit kidney cortex by using a Ca-binding medium and gentle mechanical forces. The suspension was subjected to carrier-free electrophoresis, and several cell fractions were obtained. Proximal and distal tubule cell populations could be identified by their morphology. Renin-containing cells were located by means of radioimmunoassay. The morphology of the cells and their vitality (uridine incorporation) are discussed.

Renin release from isolated rat glomeruli.

1. By the use of a mechanical graded sieving technique a high yield of isolated glomeruli has been obtained from rat kidny. 2. Microscopy and renin assay have shown the presence of renin-containing juxtaglomerular cells attached to these glomeruli. 3. The viability of isolated glomeruli has been confirmed by the ability of the cells to survive and divide in tissue culture and by their exclusion of vital dyes. 4. In superfusion after washout of extracellular renin, the glomeruli actively release constant amounts of renin over 3 h in direct proportion to the number of superfused. 5. Decreasing sodium concentration from 140 to 110 mol/l with constant osmolarity of 305 mosmol/l stimulated renin release by a direct effect on juxtaglomerular cells. 6. Catecholamines stimulated renin release in vitro in proportion to the potency of their action on beta-adrenoreceptors. 7. The system of superfusion of isolated glomeruli provides a technique for studying the influence of mediators leading to renin release acting directly on juxtaglomerular cells, independent of pressure change, tubular sodium, the sympathetic nervous system and circulating hormones.

Mechanisms regulating renin release.

Mechanisms regulating renin release.