Peripolar cells in guinea pigs under experimental hyperplasia of juxtaglomerular cells induced by long-term, low-dose calcium condition.

The peripolar cell was described in the glomeruli of sheep by Ryan et al. in 1979 and these cells have subsequently been detected in many species (Ryan et al. 1982; Gall et al. 1986; Hanner et al. 1980). The peripolar cells are located at the junction between the podocytes of the glomerular capillaries and the epithelial lining of Bowmann's capsule, encircling the hilar region of the glomerular tuft. Functionally, the peripolar cells have been considered to be a part of the juxtaglomerular apparatus but the precise nature of the cells has not been identified (Gardiner et al. 1985). Recently, it has been found that an antibody against rat urinary kallikrein reacts positively with sheep peripolar cell (Gall et al. 1984). This finding has led to the suggestion that the peripolar cells may influence the renin secretion through the kallikrein-kinin system. In our experiments with long-term low-calcium condition accompanied with hyperplasia of juxtaglomerular cells the peripolar cells were easily detected. The results suggests that the increase in the number of peripolar cells is closely related to the hyperplasia of juxtaglomerular cells.

Necklace-like detachment of endothelial cell layer from arterial wall under low-calcium condition.

The diversified morphological manifestations in various tissues and organs obtained by administration of differing amounts of calcium chelating agents were reported in previous papers (Yamaguchi et al 1981 a & b; 1982; 1990; 1993). In our recent research described here, administration of a moderate dose of Na2EDTA over the short term demonstrated necklace-like detachment from the arterial wall without disruption of the endothelial cell chain. Intercellular spaces in the media just beneath the detached endothelial cell layer was stained strongly with colloidal iron staining. Electron microscopic observation revealed that the detached endothelial cells showed a lot of elongated anchoring villi from the basal surface, usually seen at the luminal surface, adhered to the degenerative and thin flattened internal elastic lamellae. The alteration of the colloidal iron staining of the vascular wall under the low-calcium condition is suggested to be induced by loosening of the molecular structure of glycosaminoglycans (GAGs) as well as glycoproteins (GPs), comprising the important component of the intercellular matrix and elastic lamellae, which would induce a change in their pasty or viscous character. This would be an accelerative factor for detachment of endothelial cells. Moreover, the lack of the waving of the internal elastic lamellae, trapping of endothelial cytoplasmic processes among them, would play the decisive role in the total detachment of the endothelial cell layer. On the other hand, the low-calcium condition did not adversely influence the joining of endothelial cells. The pathognomatic mechanism will be discussed, with a comparison made to the angiolytic changes provoked by a large amount of Na2EDTA.

Experimental idiopathic dilated cardiomyopathy under low-calcium condition.

Administration of long-term, low-dose Na2EDTA leads to moderate or severe thinning of the right ventricular wall with or without rupture. These morphological manifestations are known to be site-dependent on the constriction of pulmonary arteries (Yamaguchi et al. 1993a). They sometimes ensue from aneurysmal dilatation and/or plexiform-like-lesion in a pulmonary artery (Yamaguchi et al. 1993b). The present contribution reports that experimental animals who survived for a longer period, maximum for 6 months, showed dilatation of the left ventricle with a mode-rately thin ventricular wall as well as right ventricular changes, which are similar to the morphological manifestations in idiopathic dilated cardiomyopathy.

Experimental study on the hyperplasia of juxtaglomerular cells under low-dose, long-term administration of calcium chelating agents. Similar to the morphological manifestation of Bartter's syndrome.

Bartter's syndrome is a genetic disorder which has very rarely been clinically encountered. However, it is of specific interest with respect to the hormonal layer of the kidney, including renin, angiotensin and aldosterone as well as biological alteration of the various electrolytes. The fundamental morphological manifestation of this disorder is known to be hyperplasia of juxtaglomerular cells, although, until now, no experimental studies on this condition have been reported. Demonstrated in this initial study is the remarkable hyperplasia of the juxtaglomerular cells in all terminal portions of the afferent glomerular arterioles situated near the hilum of the glomerular tuft, using a low-dose, long-term administration of calcium chelating agents. This hyperplasia reported in this paper may lead to a new procedure in the analysis of this syndrome.

Study of morphological manifestations of pulmonary arteries in experimental pulmonary hypertension provoked by administration of long-term, low-dose Na2EDTA--especially in aneurysmal changes and plexiform-like lesions.

In a previous paper (Yamaguchi et al. 1991) we informed that the administration of 1 ml. of 6% Na2EDTA every day intraperitoneally for two months led to the death of the guinea pigs, and autopsy revealed that the causes of death were right ventricular rupture ("rupturing") or severe right heart failure which was observed as extraordinary dilatation of the right ventricle ("non-rupturing"). The two different morphological causes of death were site dependent on the constriction of the pulmonary arteries, and the pulmonary arteries showed a fairly unique morphology. To analyze the morphological manifestations of the pulmonary arteries which were observed in the cases of extraordinarily dilated and thin ventricular luminal wall a decreased dose of Na2EDTA was administered every day for six months in order to maintain a reasonably long life of the animals through prevention of right ventricular rupture. In addition to the morphological manifestations reported in the previous paper, the longer term constriction of pulmonary arteries provoked aneurysmal changes, partially or totally, and the plexiform-like lesions which have been thought to be the most characteristic morphological one in pulmonary hypertension. The formative mechanisms are discussed.

Experimental pulmonary hypertension induced by constriction of the pulmonary arteries resulting in rupture or extraordinary dilatation of the right ventricle after administration of a little amount of Na2EDTA.

Our earlier studies on the hypocalcemic condition have focused on the histological distortion of the organ structure with the removal of the calcium ion from the molecular structure of acid mucopolysaccharides (AMPs); resulting in the sol-gel diversion of the matrix. Bivalent cationic materials including calcium are related not only to function but also to structural alteration of the living organism (Yamaguchi et al. 1978, 1981, 1982, 1985, 1991). The ionic shift from the structural phase to the functional phase induced a number of morphological distortions of the various organs. In the present paper, starting our research from a different experimental viewpoint, we decreased the Na2EDTA dose used to prevent the conventional typical tetanic shock which sometimes results in animal death. We expected this decreased dose to induce mild constriction of muscle cells. In our experiment, administration of a small amount of Na2EDTA intraperitoneally provoked animal death after 10 days to two weeks over a two-month period. In the initial phase of 10 days to two weeks, rupture of the right ventricular wall along the septum occurred at an anterior angle with moderate right ventricular dilatation and a remarkably thin ventricular wall. Characteristic of these cases was elastosis between the medial smooth muscle cells of the main pulmonary arteries accompanied by a severe degree of constriction. On the other hand, demonstrated in the delayed cases of between more than two weeks to two months there was severe dilatation of the right ventricular lumina with paper-like thinness of the wall. In these cases, the main pulmonary arteries showed rather slight constriction with scarce elastosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Dynamic aspects of AMPs in the kidney in physiological conditions--their metabolism and turnover.

The past few decades have witnessed a number of studies on AMPs in the kidney. Almost all of these studies, however, have dealt with the quantitative and qualitative analysis of AMPs in the kidney using biochemical techniques, whereas the dynamic aspect of AMPs in the kidney has been overlooked and its metabolism and turnover have never been emphasized. On the other hand, the kidneys removed from humans and experimental animals revealed a wide variety in interstitial tissue in the medulla microscopically and in the papilla of the kidney macroscopically. The reasons for these variations in the medulla, its mechanism and the matrical component have not yet been clarified. In an effort to clarify these points, we herein describe our study on the dynamic aspect of AMPs in kidney histologically in relation to their biological turnover which we employed several staining methods. Our results revealed that there was a very active turnover of AMPs present in the kidney confirming that the kidney plays an important role physiologically in AMP metabolism. The degree of the turnover of AMPs in the kidney varies from case to case. In the active phase, AMPs are excreted in the glomerulus and reabsorbed in the proximal portion of the collecting tubules. Most of the absorbed AMPs are finally drained through the lymphatic vessels in situ and a few are excreted into the urine. Contrary cases have been demonstrated, however, only were a few AMPs were noted throughout the nephrons in the kidney. AMP turnover in the kidney is unexpectedly remarkable. The medulla, which has been considered less important, in fact, plays a key role in AMP metabolism.

Renal lesions following administration of calcitonin. A consideration on the morphological similarities to IgA nephropathy.

In previous papers angiolysis of mesenteric arteries and mesangiolytic changes of renal arteries following administration of a vast amount of Na2EDTA were reported. In this study the effect of the calcium depressor calcitonin is investigated experimentally in the kidney. Long-term observation over 6 months demonstrates early stages of mesangiolysis in the renal glomeruli, morphological changes of the basement membrane and mesangial cell proliferation. Moreover, paramesangial dense deposits, probably consisting of IgA were visualized. The variable intensities of the lesions in different glomeruli and segments are very similar to those observed in IgA nephropathy.

Experimental study on fulminant angitis with fibrinoid-like degeneration.

Administration of high doses of Na2EDTA or feeding animals a low calcium diet leads to angiolytic changes of the mesenteric arteries as reported in previous papers. Slight inflammatory reactions in the arterial wall including leucocytic infiltration and exudation could be demonstrated. The reason is thought to be the lack of morphological changes of the endothelium. As far as the endothelium was concerned a lift up phenomenon of the endothelial cells and the formation of subendothelial vacuoles was observed, but no endothelial gap formation or desquamation. Administration of Na2EDTA resulted in rapid removal of calcium ions from living animals, but injurious effects on the morphology of the cells did not occur except of changes of the cellular shape, both of endothelial and smooth muscle cells. Without any morpho-functional alterations of the endothelial lining cells, severe exudation and leucocytic trapping could not be induced. The morphological changes of the vascular wall following the above procedures are said to be angiolytic and not angitic. In this experiment, dysproteinemia was provoked in Na2EDTA treated animals by repeated administration of bovine serum albumin (BSA). As a result, angitis-like lesions with severe exudation, similar to those of fibrinoid degeneration and leucocytic reaction against it, were demonstrated. These facts showed that angitis is not merely due to exogenous factors and hostal predisposition.

An experimental model of calcification in the vessel wall.

Multiple angiolytic changes of the mesenteric arteries due to administration of vast amounts of Na2EDTA into the peritoneal cavity of guinea pigs have already been demonstrated by Yamaguchi et al. (1981 a, b). In this experiment, one week after Na2EDTA administration calcium lactate was administered in the same manner. As a result calcium deposition was observed in the intimal elastic fibers, in and at the collagenous fibers and intermuscular spaces of lytic and ensuing dilatated areas of the vascular wall. This suggests that dystrophic calcification might be induced by conjugation of calcium ions to the free negative charges of acid mucopolysaccharides (aMPS) which are the main component of the above structural elements.

Experimentally induced aneurysms of mesenterial arteries. Studies on the histogenesis of acquired aneurysm.

In previous studies (YAMAGUCHI et al. 1981 a, b) we administered vast amounts of Na2EDTA into the peritoneal cavity of guinea pigs and demonstrated multiple angiolytic changes of mesenterial arteries. In this experiment, with the same procedures, aneurysm formation of these arteries was encountered based on the above angiolysis. The vascular changes described may be induced by the same mechanisms which provoked angiolysis followed by loosening of elasticity, raised blood pressure and lack of surrounding support.

Placental barrier against circulating immune complexes. A study in pregnant guinea pigs using maternal injection of horseradish peroxidase soluble immune complexes.

It is not rare that the so-called immune complex diseases (some of which were recently supposed to be induced by the biological effects of circulating antigen-antibody immune complexes) are concomitantly present in pregnant females. But there have been very few reports of congenital immune complex diseases.

Immunobiological function of the syncytiotrophoblast: a new theory.

The main purpose of this paper is to present our hypothesis concerning the antigen-antibody complex formation and the resolution system inside the syncytiotrophoblast to explain immunologic fetomaternal relationships. This hypothesis, derived from the results of our experiments, might be an answer to why the fetus is not rejected by the mother, in contradistinction to other allografts. We also believe that this hypothesis makes important contributions to the explanation of the immunologic processes of cells, i.e., those processes which work against antigens inside a living body.