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Biomedical subjects

H Yanagisawa

Publications and source records attributed to H Yanagisawa.

At least 19 recordsLinked to original sources
PubMed1998

Altered expression of endothelin-1 and endothelial nitric oxide synthase in the juxtaglomerular apparatus of rats with HgCl2-induced acute renal failure.

A progressive fall in glomerular capillary plasma flow (QA) is observed in mercury chloride (HgCl2)-induced acute renal failure (ARF) although the site of the main lesion of this ARF is the proximal tubule. To elucidate this mechanism, we examined the expression of endothelin (ET)-1 and endothelial nitric oxide synthase (eNOS) protein at the glomerulus level in the kidneys of control rats and rats with HgCl2-induced ARF. Both ET-1 and eNOS protein were detected in the juxtaglomerular cells of afferent arterioles. The expression of ET-1 was significantly increased in ARF rats when compared to control rats. Inversely, the expression of eNOS protein was markedly reduced in ARF rats as opposed to control rats. These observations suggest the participation of the vasoconstrictor, ET-1 and the vasodilator, NO in a reduction in QA observed in HgCl2-induced ARF.

Acute Kidney Injury↗
PubMed1998

Intracellular aggregate formation of dentatorubral-pallidoluysian atrophy (DRPLA) protein with the extended polyglutamine.

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder caused by the abnormal CAG triplet-repeat expansion resulting in an elongated polyglutamine (polyQ) stretch. We have recently showed that the DRPLA protein is cleaved during apoptosis by caspase-3, one of the cysteine protease family members known to be activated during apoptosis. We report here the subcellular localization of the DRPLA protein by fusing the green fluorescent protein as a tag. The full length DRPLA protein is localized predominantly but not exclusively in the nucleus regardless of the length of the polyQ stretch. In contrast, an N-terminal-deleted fragment containing polyQ produced by the proteolytic cleavage with caspase-3 is found both in the nucleus and the cytoplasm. Moreover, the same fragment with the elongated polyQ showed aggregation when overexpressed. Some cells with aggregate formation showed apoptotic phenotype. These findings raise the possibility that the DRPLA protein processed by caspase-3 may lead to aggregation of the protein resulting in the development of neurodegeneration.

Apoptosis↗
PubMed1998

Role of Endothelin-1/Endothelin-A receptor-mediated signaling pathway in the aortic arch patterning in mice.

The intercellular signaling mediated by endothelins and their G protein-coupled receptors has recently been shown to be essential for the normal embryonic development of subsets of neural crest cell derivatives. Endothelin-1 (ET-1) is proteolytically generated from its inactive precursor by endothelin-converting enzyme-1 (ECE-1) and acts on the endothelin-A (ETA) receptor. Genetic disruption of this ET-1/ECE-1/ETA pathway results in defects in branchial arch- derived craniofacial tissues, as well as defects in cardiac outflow and great vessel structures, which are derived from cephalic (cardiac) neural crest. In this study, in situ hybridization of ETA-/- and ECE-1(-)/- embryos with a cardiac neural crest marker, cellular retinoic acid-binding protein-1, shows that the migration of neural crest cells from the neural tube to cardiac outflow tract is not affected in these embryos. Immunostaining of an endothelial marker, platelet endothelial cell adhesion molecule CD-31, shows that the initial formation of the branchial arch arteries is not disturbed in ETA-/- or ECE-1(-)/- embryos. To visualize the subsequent patterning of arch vessels in detail, we generated ETA-/- or ECE-1(-)/- embryos that expressed an SM22alpha-lacZ marker transgene in arterial smooth muscle cells. Wholemount X-gal staining of these mutant embryos reveals that the abnormal regression and persistence of specific arch arteries results in disturbance of asymmetrical remodeling of the arch arteries. These defects include abnormal regression of arch arteries 4 and 6, enlargement of arch artery 3, and abnormal persistence of the bilateral ductus caroticus and right dorsal aorta. These abnormalities eventually lead to various types of great vessel malformations highly similar to those seen in neural crest-ablated chick embryos and human congenital cardiac defects. This study demonstrates that ET-1/ETA-mediated signaling plays an essential role in a complex process of aortic arch patterning by affecting the postmigratory cardiac neural crest cell development.

Animals↗
PubMed1998

Role of angiotensin II, endothelin-1, and nitric oxide in HgCl2-induced acute renal failure.

To elucidate the mechanisms underlying the development of HgCl2-induced acute renal failure (ARF), we examined the expression of endothelin (ET)-1, endothelial (e) nitric oxide synthase (NOS) and inducible (i) NOS, and a role of angiotensin II (ANG II) and tumor necrosis factor (TNF) in glomeruli and cortices from rats at 20 h after exposure of HgCl2. Prepro-ET-1 and iNOS mRNA were significantly increased in glomeruli and cortices from rats with HgCl2-induced ARF. However, eNOS mRNA was markedly decreased in glomeruli of rats with HgCl2-induced ARF. Blockade of the action of endogenous ANG II with TCV-116, an ANG II receptor type 1 antagonist, or prior administration of TNF antibody (Ab) neutralizing TNF bioactivity or aminoguanidine, an iNOS inhibitor, substantially suppressed the increase in the expression of prepro-ET-1 or iNOS mRNA seen in rats with HgCl2-induced ARF. Both TCV-116 and TNF Ab had no effects on the expression of eNOS mRNA. The abundance of ET-1, iNOS, and eNOS proteins was paralleled by the magnitude of each mRNA expression. Additionally, the aggravation of blood urea nitrogen and serum Cr observed in rats with HgCl2-induced ARF were significantly ameliorated together with the alleviation of proximal tubule epithelial cell injury when the expression of prepro-ET-1 or iNOS mRNA was blunted by prior administration of TCV-116 or prior injection of TNF Ab or aminoguanidine. These observations indicate that ANG II, ET-1, and NO may play an important role in the progression of HgCl2-induced ARF through the acceleration of proximal tubule epithelial cell injury and the deterioration of glomerular hemodynamics. In HgCl2-induced ARF, the gene expression of ET-1 or iNOS is at least in part up-regulated at the transcription level by endogenous ANG II or TNF.

Acute Kidney Injury↗
PubMed1998

Zinc deficiency aggravates tubulointerstitial nephropathy caused by ureteral obstruction.

Ureteral ligation causes tubulointerstitial nephropathy characterized by the tubular dilatation, the interstitial expansion, and a leukocyte infiltration into the tubulointerstitium. The present study was designed to explore whether zinc (Zn) deficiency affects the development of unilateral ureteral obstruction (UUO)-induced tubulointerstitial nephropathy. Compared to rats fed a standard diet, rats fed a Zn-deficient diet exhibited a greater influx of leukocytes into the tubulointerstitium of the cortex of the obstructed kidney 3 d following UUO. Furthermore, rats fed a Zn-deficient diet showed a slight invasion of leukocytes into the tubulointerstitium of the cortex of the contralateral nonobstructed kidney (CLK), although there was no infiltration of leukocytes into the CLK of rats fed a standard diet. These histological changes, however, were ameliorated by administration of enalapril, an angiotensin (ANG) I-converting enzyme inhibitor. Thus, it is suggested that Zn deficiency aggravates UUO-induced tubulointerstitial nephropathy via an increase in the action of ANG II.

Animals↗
PubMed1998

Pharmacology of endothelins in vascular circuits of normal or heterozygous endothelin-A or endothelin-B knockout transgenic mice.

Endothelin-1 (ET-1; 0.001-1 nmol) and the ETB receptor agonist IRL-1620 (0.01-1 nmol) induced a dose-dependent vasoconstriction of the arterial and venous mesenteric circuits and of the kidney in normal mice. BQ-123 (10(-7) M) or BQ-788 (10(-7) M) abolished the vasoconstriction induced by ET-1 in the arterial mesenteric and renal vasculatures without affecting that of norepinephrine (NE). In the venous mesenteric vasculature, only BQ-123 reduced the response to ET-1 but not to NE. In other experiments we compared the mesenteric and renal vascular reactivities to ET-1 and IRL-1620 in ETA or ETB heterozygous knockout mice with those of the wild-type strain. We observed a significant reduction in vascular reactivity to ET-1 but not to IRL-1620 in the arterial mesenteric and renal but not the venous mesenteric circuits of ETA knockout mice. In contrast, there was a significant reduction in vascular reactivity to ET-1 and IRL-1620 in the arterial mesenteric and renal circuits of ETB knockout mice. In the venous mesenteric vasculature, only the vasoconstriction induced by IRL-1620 was significantly reduced in the same ETB knockout strain. Our results suggest that, in the mouse, arterial mesenteric and renal vasoconstriction to ET-1 is mediated by both subtypes of ET receptors, whereas venous mesenteric vasoconstriction appears to be mediated uniquely by the ETA receptor subtype. Knockout of only one allele of the ETA or ETB gene appears to be sufficient for reduction of the ET-1 or IRL-1620 vasoconstrictor effects in the mesenteric and renal vascular beds of the mouse.

Animals↗
PubMed1998

Effects of dietary protein on eicosanoid production in rat renal tubules.

The effects of dietary protein on the in vitro production of prostaglandin (PG) E2, 6-keto PGF1alpha, and thromboxane B2 (TxB2) were examined in cortical and medullary tubules from rats fed a low (6% casein) or a high (40% casein) protein diet for approximately 8 weeks. PGE2 was a major eicosanoid produced by rat renal tubules (PGE2 > TxB2 > 6-keto PGF1alpha). Medullary tubules produced significantly greater amounts of PGE2, 6-keto PGF1alpha, and TxB2 than cortical tubules. The activity of phospholipase (PL) A2 and PLC and the levels of cyclooxygenase (COX) were significantly greater in medullary tubules than in cortical tubules. The production of eicosanoids may be increased in medullary versus cortical tubules via the greater activity of these enzymes involved in eicosanoid formation. Although there were no substantial differences in the production of PGE2, 6-keto PGF1alpha, and TxB2 between cortical tubules from rats fed a low- or a high-protein diet, significant increases in the synthesis of the three eicosanoids were observed in medullary tubules from rats fed a high- versus a low-protein diet. The activity of membrane-bound PLA2 and PLC and the levels of COX were not also substantially different between cortical tubules from rats fed a low- or a high-protein diet. However, medullary tubules had significantly greater activity of membrane-associated PLA2 and COX in rats fed a high-protein diet than in those fed a low-protein diet. The activity of PLC was comparable in medullary tubules from rats fed a low- or a high-protein diet. We conclude that a high protein intake selectively enhances eicosanoid production in rat medullary tubules probably via activation of the PLA2-COX pathway.

Animals↗
PubMed1998

Requirement of the MADS-box transcription factor MEF2C for vascular development.

The embryonic vasculature develops from endothelial cells that form a primitive vascular plexus which recruits smooth muscle cells to form the arterial and venous systems. The MADS-box transcription factor MEF2C is expressed in developing endothelial cells and smooth muscle cells (SMCs), as well as in surrounding mesenchyme, during embryogenesis. Targeted deletion of the mouse MEF2C gene resulted in severe vascular abnormalities and lethality in homozygous mutants by embryonic day 9.5. Endothelial cells were present and were able to differentiate, but failed to organize normally into a vascular plexus, and smooth muscle cells did not differentiate in MEF2C mutant embryos. These vascular defects resemble those in mice lacking the vascular-specific endothelial cell growth factor VEGF or its receptor Flt-1, both of which are expressed in MEF2C mutant embryos. These results reveal multiple roles for MEF2C in vascular development and suggest that MEF2-dependent target genes mediate endothelial cell organization and SMC differentiation.

Animals↗
PubMed1998

Cranial and cardiac neural crest defects in endothelin-A receptor-deficient mice.

Neural crest cells arise in the dorsal aspect of the neural tube and migrate extensively to differentiate into a variety of neural and non-neural tissues. While interactions between neural crest cells and their local environments are required for the proper development of these tissues, little information is available about the molecular nature of the cell-cell interactions in cephalic neural crest development. Here we demonstrate that mice deficient for one type of endothelin receptor, ETA, mimic the human conditions collectively termed CATCH 22 or velocardiofacial syndrome, which include severe craniofacial deformities and defects in the cardiovascular outflow tract. We show that ETA receptor mRNA is expressed by the neural crest-derived ectomesenchymal cells of pharyngeal arches and cardiac outflow tissues, whereas ET-1 ligand mRNA is expressed by arch epithelium, paraxial mesoderm-derived arch core and the arch vessel endothelium. This suggests that paracrine interaction between neural crest-derived cells and both ectoderm and mesoderm is essential in forming the skeleton and connective tissue of the head. Further, we find that pharyngeal arch expression of goosecoid is absent in ETA receptor-deficient mice, placing the transcription factor as one of the possible downstream signals triggered by activation of the ETA receptor. These observations define a novel genetic pathway for inductive communication between cephalic neural crest cells and their environmental counterparts.

Animals↗
PubMed1998

Dual genetic pathways of endothelin-mediated intercellular signaling revealed by targeted disruption of endothelin converting enzyme-1 gene.

Recent gene targeting studies have revealed unexpected roles for endothelins in the development of neural crest-derived tissues. Endothelin converting enzyme-1 (ECE-1) catalyzes the proteolytic activation of big endothelin-1 to endothelin-1(ET-1) in vitro. However, the importance of ECE-1 cleavage in the multiple endothelin pathways in vivo is unknown. Here we generated a targeted null mutation in the mouse ECE-1 gene. ECE-1-/- term embryos exhibited craniofacial and cardiac abnormalities virtually identical to the defects seen in ET-1 and endothelin A receptor (ETA)-deficient embryos. Epidermal melanocytes as well as enteric neurons of the distal gut were also absent in ECE-1-/- embryos, reproducing the developmental phenotype seen in ET-3-/- and endothelin B receptor (ETB)-/- mice. Surprisingly, large amounts of mature ET-1 peptide are found in ECE-1-/- embryos, indicating that non-ECE-1 protease(s) can activate ET-1 at certain sites. However, these enzymes cannot produce sufficient mature endothelin at the locations crucial for normal embryonic development. These findings reveal that ECE-1 is a bona fide activating protease for both big ET-1 and big ET-3 in vivo, and that the cell-cell communication pathways represented by the ET-1/ECE-1/ETA axis and the ET-3/ECE-1/ETB axis are each involved in the development of distinct subsets of neural crest cell lineages. Mutations in ECE-1 may cause developmental defects in humans, such as Hirschsprung disease, velocardiofacial syndrome and related neurocristopathies.

Animals↗
PubMed1998

[HgCl2-induced acute renal failure and its pathophysiology].

Mercury chloride (HgCl2) has a potent nephrotoxic effect. Most of Hg2+ existing in plasma following HgCl2 exposure forms a complex with sulfhydryl-containing ligands such as albumin and glutathione (GSH). The Hg(2+)-GSH complex is filtered in the glomeruli of the kidney and degraded into Hg(2+)-cysteine in the proximal tubules by the combined action of gamma-glutamyl transpeptidase and dipeptidase present in the epithelial cells. The degradation product is then incorporated and accumulated into the proximal tubule epithelial cells. The accumulated Hg2+ in the epithelial cells finally causes acute tubular necrosis (ATN) by its cytotoxic effect. At present, it is believed that tubular obstruction resulting from ATN triggers the onset of HgCl2-induced acute renal failure (ARF). A progressive fall in glomerular filtration rate (GFR) contributes to the progression of HgCl2-induced ARF. The fall in GFR may be caused by an increment in afferent arteriole resistance (RA) and a decrement in the ultrafiltration coefficient (Kf) due to mesangial cell contraction. These changes in RA and Kf may be attributed to the increased action of the vasoconstrictors, angiotensin II and endothelin-1 and to the decreased action of the vasodilator, nitric oxide observed at the glomerulus level of HgCl2-induced ARF. Accordingly, the imbalance between these vasoactive substances appears to play an important role in the progression of HgCl2-induced ARF due to reducing GFR. Further studies, however, remain to elucidate the mechanisms involved.

Acute Kidney Injury↗
PubMed1998

Inducible nitric oxide synthase expression in mercury chloride-induced acute tubular necrosis.

To examine the mechanisms involved in the progression of mercury chloride (HgCl2)-induced acute tubular necrosis (ATN), we investigated the histopathological changes and the expression of inducible nitric oxide synthase (iNOS) mRNA and protein in renal cortices of rats at 20 hours after exposure to HgCl2. The expression of iNOS mRNA was significantly augmented in renal cortices of rats with HgCl2-induced acute renal failure (ARF). Likewise, the induction of iNOS protein was observed in damaged proximal tubule epithelial cells of rats with HgCl2-induced ARF. Pretreatment of rats with iNOS inhibitor aminoguanidine, however, suppressed the development of proximal tubule epithelial cell injury and prevented an increase in blood urea nitrogen and serum creatinine as well as resulting in a marked fall in iNOS mRNA and protein in rats with HgCl2-induced ARF. These observations indicate that the induction of iNOS may play a role in the progression of HgCl2-induced ATN through the exacerbation of proximal tubule epithelial cell damage.

Acute Kidney Injury↗
PubMed1997

Ureteral obstruction enhances eicosanoid production in cortical and medullary tubules of rat kidneys.

We examined prostaglandin (PG) E2, 6-keto PGF1alpha, and thromboxane B2 (TxB2) production in cortical and medullary tubules from sham-operated control (SOC) rats and rats with bilateral ureteral obstruction (BUO) of 24 h duration. In SOC rats medullary tubules produced significantly greater amounts of the three eicosanoids than cortical tubules. Again, the production of PGE2, 6-keto PGF1alpha, and TxB2 by cortical and medullary tubules was significantly greater in BUO rats than in SOC rats. To elucidate the mechanisms involved, we examined the activity of phospholipase A2 (PLA2) reactive against phosphatidylcholine or phosphatidylethanolamine (PE), the activity of phospholipase C (PLC), and the levels of cyclooxygenase (COX) in cortical and medullary tubules from SOC and BUO rats. In SOC rats the activity of phosphatidylcholine-PLA2 and PE-PLA2, the activity of PLC, and the mass of COX were significantly greater in medullary tubules than in cortical tubules. On the other hand, the activity of PLC in membranes of cortical tubules and the activity of PE-PLA2 and PLC in membranes of medullary tubules, which were in active location, were significantly greater in BUO rats than in SOC rats. COX levels were also significantly greater in cortical and medullary tubules of BUO rats than in those of SOC rats. Thus, we indicate that medullary tubules from SOC rats have greater production of eicosanoids through increased activity of the PLA2 and PLC-COX pathway than cortical tubules from the same group of rats. Again, in rats with BUO, the tubular eicosanoid production may be enhanced via activation of the PLC-COX pathway in cortical tubules or through activation of the PE-PLA2 and PLC-COX pathway in medullary tubules. The enhanced production of tubular eicosanoids observed in rats with BUO may affect tubular function, particularly sodium and water reabsorption.

6-Ketoprostaglandin F1 alpha↗
PubMed1996

Nonpeptide angiotensin II receptor antagonists: synthesis, biological activities, and structure-activity relationships of imidazole-5-carboxylic acids bearing alkyl, alkenyl, and hydroxyalkyl substituents at the 4-position and their related compounds.

A series of imidazole-5-carboxylic acids bearing alkyl, alkenyl, and hydroxyalkyl substituents at the 4-position and their related compounds were prepared and evaluated for their antagonistic activities to the angiotensin II (AII) receptor. Among them, the 4-(1-hydroxyalkyl)-imidazole derivatives had strong binding affinity to the AII receptor and potently inhibited the AII-induced pressor response by intravenous administration. Various esters of these acids showed potent and long-lasting antagonistic activity by oral administration. The most promising compounds were (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (CS-866) and (pivaloyloxy)-methyl esters of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[(2'-1H-tetrazol-5- ylbiphenyl-4-yl)-methyl]imidazole-5-carboxylic acid (26c). A study involving stereochemical comparison of 26c with the acetylated C-terminal pentapeptide of AII was also undertaken.

Acetylation↗
PubMed1996

A unique origin and multistep process for the generation of expanded DRPLA triplet repeats.

Dentatorubral and pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder associated with the expansion of a CAG repeat at chromosome band 12p13. Epidemiological studies have demonstrated an increased prevalence of DRPLA in Japan, although several DRPLA kindreds of non-Japanese ancestry have been identified. To define the molecular basis for this geographic variation in prevalence, we have analyzed haplotypes around the repeat in several different ethnic groups. Two intragenic biallelic polymorphisms distinguished three haplotypes, each of which formed a predominant haplotype found in the three major racial populations. All the expanded repeats of Japanese and Caucasian patients studied were associated with a particular haplotype, which otherwise was associated with longer repeats commonly found in Asians. Our results support a multi-step model for repeat expansion, and suggest that expanded DRPLA repeats may have evolved from an ancient chromosomal haplotype of Asian origin. We also propose that a combination of a highly polymorphic microsatellite marker with relatively stable biallelic markers in a range of PCR amplification is a powerful tool for studies on human genome diversity, which may reveal the ancient human migration and the formation of ethnic groups.

Black or African American↗