Search PubMed⌕ Search

Biomedical subjects

I Ichikawa

Publications and source records attributed to I Ichikawa.

At least 55 records · Page 3Linked to original sources
PubMed1997

Targeting deletion of angiotensin type 1B receptor gene in the mouse.

We null mutated the mouse angiotensin type 1B (AT1B) receptor gene (Agtr1b) by gene targeting. To identify the specific cell types carrying high Agtr1b gene transcriptional activities, the AT1B coding exon was replaced with a reporter gene, lacZ. In 6- to 8-wk-old Agtr1b -/- mice, high AT1B transcriptional activity was observed in adrenal zona glomerulosa cells and the testis, including mature and immature spermatic cells, whereas low activity was detected homogeneously in anterior pituitary cells and choroidal plexus vessel walls. A similar pattern was observed in Agtr1b +/- mice with less intensity. Microscopically, the anterior pituitary, heart, adrenal, zona glomerulosa, kidney, and the testis of Agtr1b -/- mice were intact and were indistinguishable from those of Agtr1b +/+ mice. Systemic blood pressure was comparable in Agtr1b -/- and Agtr1b +/+ mice. Moreover, plasma aldosterone level was comparable between the two mouse groups. No compensatory enhancement of AT1A mRNA was found in the kidney and adrenal gland of Agtr1b -/- mice. The observed absence of the abnormal phenotypes in Agtr1b -/- mice, which have been described for homozygous angiotensinogen null mutant mice, indicates that 1) AT1A receptors can take over the role of AT1B receptors in Agtr1b -/- mice or 2) functionally significant non-AT1, non-AT2 receptor(s) may exist for the action of angiotensin.

Aldosterone↗
PubMed1997

Targeting the genes of angiotensin receptors.

Gene targeting technology has produced mutant mice carrying selective null-mutation of the genes for the components of the renin-angiotensin system. Angiotensinogen null-mutant mice showed not only severe hypotension, but also several abnormal phenotypes in the kidney, including juxtaglomerular (JG) cell hypertrophy, renal arterial hypertrophy, and hypoplastic papilla. Although angiotensin type 1A (AT1A) receptor is by far the most predominant in mice, the phenotypes of AT1A null-deletion mice are much milder than those of angiotensinogen null-mutant mice. Because renin and angiotensin (ANG) production is upregulated in AT1A null-mutant mice, it is conceivable that the AT1B receptor provides compensation for the lost functions of AT1A. The observations in mice with complete absence of a gene product have not elucidated whether the abnormal phenotypes reflect direct effects caused by lack of local tissue action of ANG II or a secondary effect caused by changes in systemic milieu. We have developed chimeric mice that are made up of a mix of clusters of wild-type cells: cells homozygous for AT1A gene deletion. Within a given chimeric mouse, the expressions of renin mRNA and protein are identical between wild-type and mutant cells. In addition, all of the chimeric mice lack the renal arterial lesion observed in standard AT1A null-mutant mice. These findings indicate that both JG cell hypertrophy and renal vascular lesions are caused by systemic, rather than local, mechanism(s).

Angiotensin II↗
PubMed1997

Role of angiotensin: insight from gene targeting studies.

We and others have recently produced, by gene targeting, several strains of mice deficient of a specific gene within the renin-angiotensin system. Detailed examination of these mutant mice not only confirmed the well-known blood pressure raising action of angiotensin II, but also revealed several important biological functions of angiotensin II that have not been well recognized, most notably the role in the ontogenesis of the kidney. Since gene targeting causes complete inactivation of the targeted gene, this approach also allows us to address the question, "is angiotensin really essential for the induction of aldosterone during ECF volume depletion?" In our studies, we obtained unequivocal evidence indicating that angiotensin is not essential, but instead, potassium becomes an effective regulator for aldosterone during extracellular fluid (ECF) volume depletion through mechanisms that are indistinguishable from those of angiotensin, that is, selective stimulation of aldosterone synthetase and proliferation of zona glomerulosa cells within the adrenal gland. In this context, angiotensin can be regarded as a modifier of K-dependent aldosterone regulation.

Angiotensin II↗
PubMed1996

What influences social skills in patients with schizophrenia? Preliminary study using the role play test, WAIS-R and event-related potential.

Persons with schizophrenia exhibit disabilities which profoundly affect their social and independent living skills, and social skills training is expected to be an effective treatment for reducing the level of severity of disabilities. Many factors may influence usage and learning of social skills; little is definitively known regarding which disabilities related to schizophrenia compromise social skills. The present report deals with factors affecting social skills. Twenty persons with schizophrenia (DSM-III-R) were tested using a Japanese version of the role play test, the reliability and validity of which were verified. Subjects were also tested using BPRS, auditory event-related potential (ERP) and WAIS-R. Nonverbal skills showed significant positive correlation with the amplitude of the N1 ERP component and age of onset, and 59% of the variance of nonverbal skills was accounted for by these factors using multiple regression analysis. Nonverbal skills are at least partially based on either automatic discriminating processes or selective attention, reflected in N1A. Information receiving and processing skills showed significant positive correlation with Performance IQ and Global Assessment of Functioning, and 61% of the variance of receiving and processing skills was accounted for by BPRS score, PIQ score and age. These skills are not directly related to elementary cognitive function as assessed by analyzing, for example, the ERP P3 component, but are based on more complex neuropsychological function.

Adult↗
PubMed1996

Chimeric mice carrying 'regional' targeted deletion of the angiotensin type 1A receptor gene. Evidence against the role for local angiotensin in the in vivo feedback regulation of renin synthesis in juxtaglomerular cells.

We have developed chimeric mice carrying 'regional' null mutation of the angiotensin type 1A (AT1A) receptor, the AT1 receptor subtype exclusively present in mouse juxtaglomerular (JG) cells. The chimeric mouse (Agtr1a -/- <--> +/+) is made up of wild-type (Agtr1a +/+) cells or cells homozygous for Agtr1a deletion (Agtr1a -/-). In the latter, the AT1A coding exon was replaced with a reporter gene, lacZ. In Agtr1a -/- <--> +/+ mice, these two clones of cells are found to be clustered and display patchy distributions in the kidney and heart. Tracking of lacZ activities in hetero- (Agtr1a +/-) and homozygous (Agtr1a -/-) deletion mutant offspring from Agtr1a -/- <--> +/+ mice revealed that the promoter activity of Agtr1a is localized in JG cells, afferent arteriolar walls, glomerular mesangial region and endothelial cells, and apical and basolateral proximal tubule membranes. The JG apparatuses of Agtr1a -/- mice are markedly enlarged with intense expression of renin mRNA and protein. In Agtr1a -/- <--> +/+ mice, these changes were proportional to the degree of chimerism. Within a given Agtr1a -/- <--> +/+ mouse, however, the degree of JG hypertrophy/hyperplasia and the expression of renin mRNA and protein were identical between Agtr1a +/+ and Agtr1a -/- cells. Thus, in the in vivo condition tested, the local interaction between angiotensin and the AT1 receptor on the JG cells has little functional contribution to the feedback regulation of JG renin synthesis.

Angiotensins↗
PubMed1996

Focal segmental glomerulosclerosis.

Over the last 2 decades, we have learnt that focal segmental glomerulosclerosis (FSGS) is a ubiquitous phenomenon underlying the progressive deterioration of many different types of renal diseases in both pediatric and adult populations. FSGS may also be the primary renal lesion, whether in new disease entities such as glycogen storage disease and human immunodeficiency virus infection, or in idiopathic FSGS. Although the mechanism which triggers the development of primary FSGS still remains unknown, laboratory and clinical studies have identified several key pathophysiological events leading to end-stage renal disease. While therapeutic modalities have not changed remarkably, a recent study, although uncontrolled, demonstrated an impressive efficacy of intravenous steroid pulse therapy in inducing remission. Nevertheless, it remains largely unknown whether such a forced remission decreases the overall risk of developing chronic renal failure. Studies have revealed an important pathophysiological role of angiotensin and the therapeutic efficacy of angiotensin converting enzyme inhibitors in progressive loss of renal function in diseases where glomerulosclerosis is secondary; however, it remains to be verified whether these results hold true in primary FSGS. As a result of the improvement in allograft survival rate, the benefit of renal transplant outweighs the risk of recurrence of FSGS, hence transplantation continues to be a vital therapy for FSGS patients who have reached renal failure. Thus, FSGS is not one disease, but rather a range of lesions seen in many settings. The type of lesions and the patient's unique genetic factors contribute to prognosis, and also may dictate choice of optimum therapy.

Animals↗
PubMed1996

Angiotensin I converting enzyme gene polymorphism in non-insulin dependent diabetes mellitus.

A total of 168 patients with non-insulin dependent diabetes (NIDDM) followed over 10 years were recruited in this study. The patients were divided into two groups: Group 1 patients had a stable renal function (N = 96) and Group 2 had a declining renal function (N = 72). Group 1 included those whose serum creatinine was normal five years ago but had increased to > or = 2 mg/dl or those who has reached end-stage renal failure (requiring dialysis) by the time of study. All patients were genotyped for the insertion/deletion (I/D) polymorphism of the ACE gene, the M235T polymorphism of the angiotensinogen (Atg) gene and the A1166C polymorphism of the angiotensin II type 1 receptor (AT1) gene. The genotype frequency distributions of M235T Atg and the A116C AT1 gene polymorphisms were not different between Group 1 versus Group 2. While the frequency of the ACE DD genotype in Group 1 (7.3%) was comparable to that of the general population, the DD frequency was significantly higher in Group 2 (26.4%) than in Group 1 (odds ratio, 4.56; 95% confidence interval, 1.80 approximately 11.56, P < 0.001). Among all 168 patients studied, the renal survival rate was significantly lower among DD than ID (P < 0.005) or II patients (P < 0.001). In patients with a declining renal function (Group 2), those with the DD genotype had a significantly shorter time interval from onset of diabetes to the initiation of dialysis (13.4 +/- 1.4 years) than those with ID (20.7 +/- 1.2 years, P < 0.01) or II genotypes (17.5 +/- 1.1 year, P < 0.01). Analysis of the clinical course of the three ACE genotypes revealed that the majority (95%) of patients with the DD genotype who had albuminuria progressed to end-stage renal disease within 10 years of diagnosis of diabetes. Our analysis also revealed that initiation and continuation of dialysis are associated with a progressive decrease in the frequency of the DD genotype. These results indicate that, in NIDDM, the ACE DD genotype has a high prognostic value for progressive deterioration of renal function. Moreover, the DD genotype appears to increase the mortality once dialysis is initiated.

Albuminuria↗
PubMed1996

Angiotensin converting enzyme gene polymorphism: potential silencer motif and impact on progression in IgA nephropathy.

Since the renin angiotensin system (RAS) is established as an important factor in renal disease progression, we determined whether RAS alleles that have been linked to variability in outcome in several cardiovascular diseases also affect progression of IgA nephropathy. These genetic variants include: (1) angiotensin I converting enzyme deletion polymorphism in intron 16 (ACE I/D), reported to be associated with increased risk of myocardial infarction as well as left ventricular hypertrophy; (2) a point mutation in the angiotensinogen (Agt) gene resulting in a methionine to threonine substitution at residue 235 (M235T), reported to be associated with hypertension in Caucasians; and (3) an angiotensin receptor type I (ATR) A to C transition at bp 1166 (A1166C) which shows synergy with the deleterious effects of the ACE DD genotype in myocardial infarction. We examined these polymorphisms by PCR amplification of genomic DNA samples from 64 Caucasian patients in the USA (age 6 to 83 years) with biopsy-proven IgA nephropathy whose renal status was followed for an average of almost seven years. Patients who presented with and maintained normal serum creatinine (Cr, < 1.5 mg/dl), had ACE genotype frequencies of II:35%, ID:61%, DD:4%. By contrast, in patients with progression (initially normal Cr increased to a mean of 4.5 +/- 0.86 mg/dl), ACE genotype frequencies were II:22%, ID:44%, DD:33% (P = 0.057 by Fishers's exact test, vs. non-progressors). The association of the DD genotype with progression was even more striking when patients with other risk factors (hypertension and/or heavy proteinuria) were excluded. In this subgroup, the genotype frequencies in patients with stable creatinine versus those with deterioration in renal function was 53%, 47%, and 0% versus 0%, 40%, and 60%, respectively, for II, ID, and DD genotypes (P = 0.009 by Fisher's exact test, progressors vs. non-progressors). Further, sequence analysis of the I gene polymorphism revealed a potential 13 bp silence motif. Neither the Agt 235T nor the ATR A 1166C gene variants, however, was associated with deterioration of renal function. Taken together, these results indicate that, although polymorphism in each of the three genes in the RAS system has been linked to cardiovascular diseases, only the ACE I/D polymorphism is associated with progressive deterioration in renal function in IgA nephropathy. Since previous observations link ACE polymorphism with ACE activity, these findings imply a widespread importance of ACE in modulating destructive processes in different organs.

Alleles↗
PubMed1996

Angiotensin in progressive renal diseases: theory and practice.

Experimental studies indicate that Angll is involved in the process of tissue destruction in chronic renal diseases. This notion has been verified in a number of small-to large-scale clinical studies using angiotensin (ANG) I converting enzyme inhibitors (ACEI). Although the repertoire of the pathophysiologic cascade underlying the progressive destruction of renal tissue has continued to expand over recent years, from proteinuria and physical forces to growth factors and metalloproteinase disregulations, studies now suggest that Angll is involved in many, if not all, of these processes. Because these expanded pathophysiologic potentials of Angll are based primarily on observations in vitro, their significance in vivo, and in humans in particular, needs to be established. Recent studies in animals and humans indicate that the role of Angll in renal tissue destruction is subject to the modulation of multiple environmental and genetic factors, such as dietary habit and ACE genotype. Further delineation of the role of Angll in this respect for specific renal diseases and patients will enable us to design an efficient therapeutic intervention for this otherwise most complex problem of today's nephrology.

Angiotensin II↗
PubMed1996

Angiotensin II receptors and renal hemodynamics and function.

The biologic action of angiotensin-converting enzyme (ACE) includes conversion of angiotensin 1 to angiotensin II (A II) and degradation of bradykinin. Thus, pharmacologic blockade of ACE is expected to augment endogenous bradykinin activity. A study using a specific bradykinin inhibitor revealed that the activation of bradykinin by an ACE inhibitor has the potential to affect the function of the kidney in several ways. It has been shown in vitro that bradykinin is a highly selective efferent (vs. afferent) arteriolar dilator. An in vivo study using both ACE inhibitors and bradykinin antagonists demonstrated that, through this efferent-arteriolar dilating effect, the bradykinin activated by ACE inhibition causes a profound reduction in glomerular pressure. In contrast, the latter phenomenon is absent during administration of an angiotensin II type 1 (AT1)-receptor antagonist, a finding consistent with the notion that AT1 antagonists are devoid of kininase inhibitory action. Due to this difference, AT1 antagonists appear to be inherently better A II inhibitors than ACE inhibitors where glomerular filtration is concerned. This speculation was verified in an acute experimental setting. It is conceivable, however, that the relatively high glomerular pressure maintained during AT1-antagonist administration may have different effects on the kidney in the long term, because the salutary effect of ACE inhibition to protect kidneys from progressive damage in chronic renal disease is attributed in part to its potent glomerular-pressure-lowering effect. The long-term effects of losartan in the kidney will need to be examined in human studies.

Angiotensin II↗
PubMed1995

Effects on blood pressure and exploratory behaviour of mice lacking angiotensin II type-2 receptor.

There are two major angiotensin II receptor isoforms, AT1 and AT2. AT1 mediates the well-known pressor and mitogenic effects of angiotensin II, but the signalling mechanism and physiological role of AT2 has not been established. Its abundant expression in fetal tissues and certain brain nuclei suggest possible roles in growth, development and neuronal functions. Here we report the unexpected finding that the targeted disruption of the mouse AT2 gene resulted in a significant increase in blood pressure and increased sensitivity to the pressor action of angiotensin II. Thus AT2 mediates a depressor effect and antagonizes the AT1-mediated pressor action of angiotensin II. In addition, disruption of the AT2 gene attenuated exploratory behaviour and lowered body temperature. Our results show that angiotensin II activates AT1 and AT2, which have mutually counteracting haemodynamic effects, and that AT2 regulates central nervous system functions, including behaviour.

Angiotensin II↗
PubMed1995

Developmental expression of renal angiotensin II receptor genes in the mouse.

The cellular distribution of angiotensin II type 1 (AT1) and type 2 (AT2) receptor mRNA was examined in mouse kidneys at several embryonic stages (12 to 18 days; 19 days = full term) and up to three weeks after birth by in situ hybridization. The expression of both AT1 and AT2 mRNAs appeared simultaneously at 14 days of gestation. However, their distributions were contrasting: AT1 mRNA was expressed in mature glomeruli and maturing S-shaped bodies throughout the stages examined. AT1 expression was also detected at 16 days of gestation in the proximal and distal tubules and peaked at the end of gestation. Both the temporal and spatial expression of AT1 coincide with the differentiation and proliferation of glomerular mesangial and tubular cells during nephrogenesis. In contrast, AT2 mRNA was present only in the mesenchymal cells adjacent to the stalk of the ureter bud at early developmental stages, and, later, extended to the mesenchymal cells located near, but outside, the nephrogenic area of superficial cortex and also the cells between collecting ducts. AT2 expression in these regions decreased markedly within three weeks after birth. Temporally and spatially, AT2 mRNA expression coincides with the epithelial-mesenchymal interactions that take place during early phases of nephrogenesis. The site of AT2 expression also overlaps closely with that of a specific group of cells which undergo apoptosis following nephrogenesis. Thus, contrary to current belief, the activation of AT1 and AT2 genes takes place in different cell types of the kidney during embryonic development, and thereby conceivably contributes to the ontogeny of those specific renal cells.

Angiotensin II↗
PubMed1995

Strategic locus for the activation of the superoxide dismutase gene in the nephron.

Upon exposure to a transient ischemia, the distal tubule of the kidney often escapes the severe damage which afflicts the proximal tubule. To ascertain whether this feature of the distal tubule is attributable to its intrinsic cellular properties, we focused on two pairs of unique tubule segments; distal versus proximal convoluted tubules in the superficial cortex and distal versus proximal straight tubules in the outer stripe of the outer medulla. These tubules were chosen because, firstly, they can be identified by morphology and immunostaining, and secondly, each pair has the same anatomical relationship to the circulation. Detailed morphometric analyses were performed six hours following unilateral transient ischemia in adult rats to semiquantitate the local tissue damage in these specific nephron segments. The architecture of the distal convoluted and straight tubules was remarkably well preserved, contrasting to the moderate to extensive necrotic changes seen in the proximal tubules. In search of the potential intrinsic cellular mechanism that underlies the observed difference, we examined the segmental distribution along the nephron of manganese superoxide dismutase gene transcripts by in situ hybridization. This antioxidant enzyme gene was expressed primarily in the distal tubules with contrastingly low levels of expression in the proximal tubules. Moreover, following ischemia-reperfusion, this distal tubule-dominant pattern was further accentuated immediately following reperfusion. The study indicates that the marked difference between the proximal and distal tubules in their susceptibility to injury in vivo is attributable to their intrinsic cellular properties, which include the local level of antioxidants.

Animals↗