Morphology, physiology, and molecular biology of renin secretion.
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Humans↗
Biomedical subjects
R Taugner
Publications and source records attributed to R Taugner.
Renin-positive granulated Goormaghtigh cells. Immunohistochemical and electron-microscopic studies on biopsies from patients with pseudo-Bartter syndrome.
It is difficult to distinguish between Goormaghtigh cells (G-cells) and media cells of the glomerular arterioles at the border of the Goormaghtigh cell field. Consequently, it has been unclear whether renin-positive G-cells are normally present and also whether renin-producing cells are recruited from the pool of renin-negative G-cells upon stimulation of the renin-angiotensin system (RAS). In the present study, immunohistochemical and electron-microscopic experiments have been carried out on serially sectioned kidney biopsies from four patients with pseudo-Bartter syndrome. The results strongly suggest that with long-lasting stimulation of the RAS all renin-negative ("secretory resting") G-cells are ultimately converted into renin-producing granular cells.
Adult↗
Macroautophagic phenomena in renin granules.
The secretory granules of murine epithelioid cells take up and probably degrade mitochondria; they thus appear to have macroautophagic properties. As renin granules also have other properties uncommon for secretory granules, they are suggested to fulfill functions in these cells otherwise reserved for lysosomes.
Adrenalectomy↗
Hypothetical interpretation of the calcium paradox in renin secretion.
Most renin-positive cells of the preglomerular arteriole are intermediate in morphological appearence between smooth muscle cells and epithelioid cells. Intermediate cells contain, in addition to secretory granules, contractile proteins arranged as a sublemmal network. The paradoxical (inhibitory) role of calcium in renin secretion is explained, on the basis of these findings, by an increased tone of the sublemmal network; this might impair the preexocytotic access of renin granules to the cell membrane.
Animals↗
Interzonal and intrazonal heterogeneities in the renin status of the preglomerular arterioles in five species.
In five species (mouse, rat, rabbit, rhesus monkey and man) the renin status of the preglomerular arterioles was examined using two immunohistochemical methods: the measurement of the renin-positive portion of the vessels, reflecting the respective number of granulated cells, and the semiquantitative assessment of the renin concentration in the juxtaglomerular epithelioid cells with antibody dilution series. The main objective of the study was to compare the interzonal with the intrazonal internephron heterogeneities, i.e. the differences between the average renin status of the preglomerular arterioles in the superficial, intermediate and juxtamedullar cortex with the differences between the renin status of the individual afferent arterioles in one and the same cortex region. In contrast to small interzonal heterogeneities, substantial intrazonal differences in the renin status of the corresponding nephrons were found.
Animals↗
The juxtaglomerular apparatus in Bartter's syndrome and related tubulopathies. An immunocytochemical and electron microscopic study.
A comparative immunocytochemical and electron microscopic study was performed on renal biopsies from two children with classical Bartter's syndrome (BS) and three children with a recently described variant, the so-called hyperprostaglandin E-syndrome (HES). Compared to age-matched controls, kidney specimens from patients with BS and HES disclosed a marked hypertrophy and hyperplasia of the juxtaglomerular apparatus (JGA). In addition, in HES focal tubular and interstitial calcifications accompanied by interstitial fibrosis and tubular atrophy were noted. On immunocytochemistry, chronic stimulation of the JGA in BS and HES was characterized by an increase in the number of renin-positive cells, particularly in the media of afferent arterioles, but also in efferent arterioles and in the glomerular stalk. The length of the renin-positive portion of the preglomerular arterioles was significantly increased when compared to controls (100 +/- 32 vs. 49 +/- 17 microns; p less than 0.001). In addition, the immunoreactivity of individual renin-positive cells was markedly enhanced. On electron microscopy, "hypertrophy" of the RER and of Golgi complexes with paracrystalline deposits in dilated RER cisterns and protogranules indicated an increased renin synthesis. Renin could be identified in mature secretory granules as well as protogranules by immune electron microscopy. Angiotensinogen was present in hypertrophied epithelial cells of Bowman's capsule. Converting-enzyme reactivity was observed in controls as well as in BS and HES in the brush border of the proximal tubule. In contrast to previous reports, Angiotensin II was completely negative in control as well as in diseased kidneys. We conclude from our results that both BS and HES are characterized by a marked activation of the JGA and severe stimulation of the renin-angiotensin system. Since activation of this system, however, leads--independently of the primary stimulus--to qualitatively very similar morphological reactions, these results do not implicate a common pathogenetic mechanism to both conditions.
Bartter Syndrome↗
Cytoplasmic sequestration phenomena in smooth muscle cells of kidney resistance vessels and epithelioid cells of the juxtaglomerular apparatus.
The occurrence of vacuoles in cells of contractile tissues and especially in media cells of resistance vessels has been known for quite some time. Recently, it has been widely accepted that these vacuoles, characteristically lined by a double membrane, result from herniation of one vascular smooth muscle cell into the other as a result of vasoconstriction. In our electronmicroscopic investigations we found double membrane-bounded vacuoles not only in kidney resistance vessels of rats and mice under conditions of vasoconstriction, but also in control animals and animals with maximal renal vasodilation. Part of our observations are compatible with the assumption that such vacuoles arise from a damage of club-shaped, musculo-muscular contacts due to shape changes of media cells during maximal vasoconstriction or vasodilation. However, serial thin sectioning revealed that some of the cytoplasmic vacuoles have no connections with neighbouring cells. This finding and various parallels to the generation of autophagic vacuoles indicate that the so-called herniations may also represent demarcations of large cytoplasmic areas within an individual cell. Irrespective of the origin of these vacuoles, their contents show different stages of deterioration. At later stages, the vacuoles appear to be adjacent, with only one membrane, to the extracellular space, into which they are believed to discharge finally. Cytoplasmic vacuolization has not only been observed in smooth muscle cells, but also in juxtaglomerular epithelioid cells of the afferent arteriole. Here the vacuoles-besides other organelles--also contain secretory granules; it is therefore proposed that autophagic phenomena with final extrusion of cytoplasmic material may be involved in the programmed down-regulation of the granular renin store following inhibition of renin synthesis and secretion.
Animals↗
On the character of the secretory granules in juxtaglomerular epithelioid cells.
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Angiotensin II↗
Morphology of electrophysiologically identified baroreceptor afferents and second order neurones in the brainstem of the cat.
Baroreceptor afferent fibres and second order baroreceptor neurones were identified by their discharge pattern and were intracellularly injected with horseradish peroxidase. Three afferent fibres and three second order neurones were reconstructed by camera lucida drawings from serial sections of the brainstem. The afferent fibres were classified as A delta-fibres and had terminal arborizations with synaptic boutons in the dorsomedial region of the nuclei of the solitary tract (TS). The afferent fibres had additional collaterals with a medial projection to the commissural nucleus and in a direction lateral to the TS. The terminals of these collaterals could not be demonstrated. The second order neurones were located in the same dorsomedial region as the synaptic boutons of the afferent fibres. Neurones were small and spindle-shaped with two primary dendrites: one dendrite projected cranially along the medial border of the TS, and the second one projected caudally and medially into the commissural nucleus. The unmyalinated axons of these neurones could be traced over a distance of 1 mm. In only one neurone could an axon collateral be detected. The axons projected dorsally around the TS in a ventrolateral direction beyond the boundaries of the nuclei of the TS. The axon collateral projected in the medial direction into the commissural nucleus. In no case were axon terminals demonstrated.
Afferent Pathways↗
The granular epithelioid cells in the kidney of the lemon sole (Pleuronectes microcephalus Donovani).
Serial sections from kidneys of 5 aglomerular lemon soles (Pleuronectes microcephalus) demonstrated the presence of anastomosing arteriolar networks in the caudal half of the organs. There was no preferred location of the networks, which were found both near the surface and in the deeper parts of the kidney. The size of the networks varied; the largest measured more than 900 micrometers in the longest axis and covered an area larger than 500,000 micrometers2, whereas the smallest measured about 60 micrometers in diameter with an area of 2040 micrometers2. The larger networks were invariably located close to large intrarenal veins. Anastomoses were found between the arteriolar networks and the peritubular capillaries and also associated with veins. The walls of the arterioles were composed of granulated epithelioid cells, exhibiting numerous intracytoplasmic granules. These granules occasionally had a rod-like appearance with a paracrystalline substructure. Using antibodies directed against murine and human renin, the epithelioid cells in the walls of the arteriolar networks and the cytoplasmic granules revealed a positive immunoreaction. The results suggest that the renin-angiotensin system in the aglomerular lemon sole may be important for both the regulation of the systemic blood pressure and the blood supply to the peritubular capillaries of the kidney.
Animals↗
Effects of extracellular osmolality on renin release and on the ultrastructure of the juxtaglomerular epithelioid cell granules.
Superfusion with hypoosmotic solutions stimulates renin release from rat epithelioid cells adherent to isolated glomeruli. This stimulatory effect may be related to the observed swelling of the secretory granules; the swelling may markedly increase the probability of pre-exocytotic fusions between the granule and cell membranes, and consequently increase the frequency of exocytotic events.
Animals↗
Myosin content and vasoconstrictive ability of the proximal and distal (renin-positive) segments of the preglomerular arteriole.
The PAP-technique and antibodies to myosin were used to demonstrate the prerequisites for vasoconstriction in the juxtaglomerular part of the preglomerular arteriole as compared with its proximal segment in rats and mice. In contrast with the myosin-positive/renin-negative proximal part of the afferent arteriole no myosin-like activity could be demonstrated in its distal, renin-positive part. In accordance, no thick myofilaments were found in fully differentiated juxtaglomerular epithelioid cells replete with mature secretory granules. Stimulation of the renin-angiotensin system was followed by an increase of the renin-positive/myosin-negative portions of the preglomerular arteriole. Marked interspecies and internephron variations in the length of this vessel segment under control and stimulated conditions were observed. The juxtaglomerular part of the preglomerular arteriole close to the macula densa seems therefore to have only limited capabilities for vasoconstriction. This finding may be of importance regarding the tubulo-glomerular feedback, a mechanism allegedly triggered by the so-called 'macula densa-signal'. It is suggested that this non-contractile segment of the afferent arteriole may represent the renal vascular receptor responsible for the increase of renin secretion during pressure reduction. Unlike the afferent arterioles, most of the efferent arterioles showed the highest level of their weak but distinct myosin-like immunoreactivity in the juxtaglomerular region, indicating some efferent juxtaglomerular vasoconstrictive ability.
Animals↗
The fate of prorenin during granulopoiesis in epithelioid cells. Immunocytochemical experiments with antisera against renin and different portions of the renin prosegment.
Comparative immunocytochemical experiments with antisera directed against renin and three synthetical peptides (Pro 1, Pro 2A and Pro 3) covering almost the entire span of human renin prosegment were performed on human kidney tissue. With anti-Pro 1, i.e. the antiserum which recognizes the NH2 terminus of human prorenin, no clear immunolabeling of juxtaglomerular epithelioid cell secretory granules could be obtained. It is therefore concluded that the corresponding portion of human prorenin may be cleaved off in the Golgi complex. After application of anti-Pro 3, the antiserum which recognizes the COOH terminus of the prosegment, only the juvenile secretory granules of epithelioid cells were consistently labeled, whereas, in contrast, some of the intermediate and most of the mature secretory granules were anti-Pro 3-negative. As the immunoreactivity of mature renin increased remarkably from protogranules to mature secretory granules, it is suggested that the cleavage of the COOH terminus of the prosegment, i.e. the activation of renin, takes place in juvenile and intermediate granules during condensation of the enzyme. The immunoreactivity of Pro 2A, corresponding to the middle portion of the prosegment, disappeared in a somewhat earlier stage of granulopoiesis than that of Pro 3. It is therefore concluded that the corresponding segmental cleavage, the result of which is a truncated version of intact prorenin, occurs in the protogranules of epithelioid cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Cytoplasmic Granules↗
Tachyphylaxis of juxtaglomerular epithelioid cells to angiotensin II. Differences between the electrical membrane response and renin secretion.
A study has been made of desensitization of the depolarizing response to angiotensin II of juxtaglomerular epithelioid and vascular smooth muscle cells in the mouse kidney afferent arteriole, of media cells from the mesenteric artery as well as of cultured smooth muscle and mesangial cells. In all cell types, desensitization to this effect of angiotensin II was observed. There was no cross-desensitization between angiotensin II and other depolarizing agonists. Hence, it is concluded that this desensitization is specific, i.e. of the tachyphylaxis type. Substances interfering with receptor recycling, such as chloroquine and monensin, did not block the recovery of the cells from desensitization after removal of the octapeptide. Desensitization to the action of angiotensin II was also observed with respect to its vasoconstrictor effect in the isolated perfused rat kidney. In contrast there was no desensitization of renin secretion in the isolated perfused rat kidney, nor in isolated hydronephrotic mouse tissue, nor in microdissected rat glomeruli.
Angiotensin II↗
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.
Angiotensin I↗
Intrarenal and intracellular distribution of renin and angiotensin.
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Angiotensin II↗
Typical and atypical aspects of renin secretion from juxtaglomerular epithelioid cells.
A survey is given about features of renin synthesis and secretion from juxtaglomerular epithelioid cells that are largely atypical as compared to those of other secretory systems. Renin-producing cells have the capability of reversible metaplastic transformation into vascular smooth muscle cells, their secretory granules are very closely related to lysosomes, and they react paradoxically, i.e. with an inhibition instead of a stimulation of renin secretion, to a rise in intracellular free Ca++. The modes of renin secretion and activation of the enzyme as well as possible mechanisms involved in adjusting the ratio of secreted active to inactive renin to the current needs of the renin-angiotensin system are discussed.
Angiotensin II↗
Development and fate of the secretory granules of juxtaglomerular epithelioid cells.
The development and fate of the secretory granules in murine, rat and human juxtaglomerular epithelioid cells were examined using ultrastructural and immunocytochemical methods. The formation of mature renin granules occurs by fusion of rhomboid protogranules followed by coalescence of their paracrystalline contents, and by the fusion of roundish juvenile granules having an amorphous internum. Protogranules with paracrystalline contents are prominent in animals with stimulated renin synthesis, indicating an overcharge in processing and/or packaging of the secretory product, renin, under these conditions. Various similarities between lysosomes/multivesicular bodies (MVBs) and juvenile renin granules have been observed. With the exception of small MVBs, no renin-negative organelles that could be regarded as lysosomes were found in epithelioid cells of mice and rats. Therefore, we suggest that renin granules are modified lysosomes. Immunocytochemical findings indicate that juvenile secretory granules of epithelioid cells represent the converting and activating compartment for prorenin. Endocytosed foreign tracers such as HRP or cationized ferritin are preferentially internalized by juvenile renin granules, which hence appear to be outstanding by their fusogeneity. Consequently, juvenile granules are probably responsible for the secretion of prorenin, and mature granules for that of active renin.
Angiotensin II↗