Development and progression of diabetic nephropathy: future interventions.
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Diabetic Nephropathies↗
Biomedical subjects
H Ha
Publications and source records attributed to H Ha.
[Anatomy cadaver ceremonies in Taiwan].
The practice of holding annual ceremonies in honor of cadaver donors in Taiwan's medical schools has a history of nearly a hundred years. It originated in Japan, where such ceremonies have been widely held in medical schools since the practice was founded by Toyo Yamawaki, who was the first medical scholar in Japan to engage in dissection of the human body and was the author of the first anatomy book to appear in Japan, the Zoshi. The practice of holding donor ceremonies was introduced into Taiwan after the Jaiwu Sino - Japanese war, when the island became a Japanese colony. The tradition was upheld in the Viceroy's Medical School, the Viceroy's College of Medicine, and Taihoku (Taipei) Imperial University College of Medicine, and continued since the restoration of Chinese power to the present. The practice of holding cadaver donor ceremonies in institutions of medical education is intended to express respect for the donor as well as to encourage the practice of cadaver donation to the benefit of medical education.
Anatomy↗
[The establishment of prescription dose system for radiotherapy on accelerator's X-ray].
This study aimed at how to calculate the prescription dose quickly and accurately. According to the conditions of radiotherapy and the dose of target point. RT-100 Radiotherapy Dosemetre, which was calibrated at the Industrial Health Institute of National Ministry of Health, was used to detect the dose distribution of special points in the phantom. Functions of dose distribution were fitted on the basis of the detected points. The dose ratio was introduced, and the calculation protocol indexed with Chinese for prescription dose was programmed. The doses of assumed points at the phantom which imitated various conditions of radiotherapy were detected. The detected doses were very close to the calculated doses, with the relative error less than 1.2%. It is concluded that dose of target point can be transformed to the prescription dose quickly and accurately with the method of dose ratio.
Particle Accelerators↗
Cytogenetical assignment and physical mapping of the human R-PTP-kappa gene (PTPRK) to the putative tumor suppressor gene region 6q22.2-q22.3.
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Chromosomes, Human, Pair 6↗
The cellular basis of cardiac allograft rejection: VIII. Mechanisms underlying delayed allograft rejection in PVG C6-deficient rats.
BACKGROUND: The delayed allograft rejection in C6-deficient PVG C6- rats compared with normal PVG rats has been attributed to the lack of alloantibody activation of the membrane attack complex of complement. As T cells alone have been shown to effect graft rejection, we examined T-cell responses in PVG C6- rats. METHODS: The cellular infiltrate and its mRNA for cytokines and effector molecules in DA heart allografts to PVG and PVG C6- rats was compared by immunoperoxidase staining and semiquantitative reverse transcriptase polymerase chain reaction. The ability of pure populations of T cells or alloantibody to mediate DA heart graft rejection in irradiated (750 rads) PVG and PVG C6- rats was also compared. RESULTS: The median rejection time of DA heart allografts was 8 days in PVG rats and 17.5 days in PVG C6-. PVG C6- rats sensitized to DA by two skin grafts rejected DA heart grafts in 5-6 days. CD3+, CD4+, CD8+, interleukin-2 receptor-positive T cell, macrophage, and natural killer cell infiltration, as well as class II major histocompatibility complex and intercellular adhesion molecule-1 up-regulation, in grafts was similar in naive PVG and PVG C6- rats. mRNA for T helper 1 cytokine interleukin-2, interferon-gamma, tumor necrosis factor-beta, macrophage molecules tumor necrosis factor-alpha, and inducible nitric oxide synthase, as well as cytotoxic T-cell effector molecules perforin and granzyme A and B, were found to be the same in the grafts from both naive PVG and naive PVG C6- rats. Thus, there appeared to be no difference in the T-cell effector response between the PVG and PVG C6- groups. There were higher alloantibody titers in PVG C6- rats than in PVG hosts. Irradiation ablated rejection and alloantibody responses and reconstitution with naive T cells alone restored rejection in both PVG and PVG C6- rats. Irradiated rats given serum from PVG rats that had rejected DA grafts did not effect rejection of DA grafts even if given naive T cells. Sensitized T cells restored second set. CONCLUSIONS: PVG C6- rats have normal T-cell responses and can mediate allograft rejection in the absence of alloantibody. The failure of PVG C6- to reject allografts rapidly may be a result of the poor clearance of alloantisera leading to enhancement of graft survival rather than a critical role for complement and membrane attack complex in acute rejection.
Animals↗
Atherogenic lipoproteins enhance mesangial cell expression of platelet-derived growth factor: role of protein tyrosine kinase and cyclic AMP-dependent protein kinase A.
Mesangial cell proliferation and extracellular matrix accumulation are fundamental in the pathogenesis of glomerulosclerosis. Platelet-derived growth factor (PDGF) is a major cytokine involved in mesangial cell proliferation, and its increased expression is seen in glomerular injury. Atherogenic lipoproteins stimulate mesangial cell proliferation and induce glomerular injury in experimental animals. We examined the effect of low-density lipoprotein (LDL) and its more atherogenic oxidized forms, minimally modified LDL (mm-LDL) and oxidized LDL (ox-LDL) on mesangial cell PDGF mRNA expression. Incubation with 2.5 to 25 microg/ml LDL or mm-LDL for 1 to 4 hours stimulated mesangial cell PDGF mRNA expression (mm-LDL 2 to 3 times greater than LDL); ox-LDL had no effect. Similarly, both LDL and mm-LDL induced mesangial cell DNA synthesis (mm-LDL 1.5 to 2 times greater). In further studies evaluating key associated intracellular signal transduction mechanisms, the protein tyrosine kinase (PTK) inhibitors herbimycin and genistein markedly decreased basal and lipoprotein-induced PDGF mRNA expression. Both pertussis toxin and isoproterenol, cyclic AMP-generating substances, stimulated PDGF mRNA expression. Preincubation with H-8 or H-89, cyclic AMP-dependent protein kinase A (PKA) inhibitors, blocked the lipoprotein-induced PDGF message, whereas preincubation with calphostin C, a protein kinase C inhibitor, did not alter LDL- or mm-LDL-mediated PDGF mRNA expression. These data suggest that the accumulation of atherogenic lipoproteins and their endogenous oxidized forms within the glomerulus may regulate mesangial cell PDGF expression and related cellular responses. These events appear to be modulated by signal transduction pathways involving PTK and PKA.
Animals↗
Value of the need for voiding cystourethrography before renal transplantation.
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Adult↗
MPK38 expression is upregulated in immature T cells activated by concanavalin A.
We have previously identified a cDNA clone from a murine teratocarcinoma PCC4 cDNA library, which we have termed MPK38 for murine protein kinase 38. MPK38 is a new member of the SNF1 serine/threonine kinase family. To understand the role of the MPK38 in thymocytes, we have investigated the level of MPK38 expression by Northern blot analysis. Interestingly, incubation of thymocytes at 37 degrees C resulted in the loss of the MPK38 transcript, however the transcript could be reinduced by treatment with Con A or PHA, but not with PMA and growth factors such as IL-2, IL-7, TGF-beta, TNF-alpha, and EGF. In addition, stimulation of mature T cells from the spleen with Con A failed to reinduce the MPK38 transcript, indicating a developmental regulation of MPK38 expression, whereas non-T cell populations significantly reinduced the transcript. These results suggest that MPK38 may play a functional role as one of the signal regulators in early T cell activation and, potentially, certain lineages of hematopoietic cell activation induced by Con A.
Animals↗
Sequential effects of high glucose on mesangial cell transforming growth factor-beta 1 and fibronectin synthesis.
BACKGROUND: Transforming growth factor (TGF)-beta is recognized as the final common mediator of the principal lesions of diabetic nephropathy such as renal hypertrophy and mesangial expansion. To gain better understanding of the temporal relationships between high glucose (HG) and mesangial cell (MC) TGF-beta 1 synthesis and between TGF-beta 1 and extracellular matrix (ECM) synthesis, the present study examined early and sequential effects of HG on TGF-beta 1 and fibronectin (FN) mRNA expression and protein synthesis. METHODS: Confluent primary rat MC was stimulated with 5.6 (control) or 30 (high) mM glucose after synchronizing the growth by incubation with serum-free media for 48 hours. RESULTS: Mesangial cell TGF-beta 1 mRNA expression increased significantly in six hours and continued to increase until 48 hours in response to HG. The level of TGF-beta 1 mRNA was 1.5-fold higher than that of control glucose at six hours and 1.8-fold at 48 hours. TGF-beta activity in heat-activated conditioned media under HG increased 1.5- and 1.6-fold at 24 and 48 hours, respectively, compared to control glucose. FN mRNA increased significantly at 24 and 48 hours and 1.4-fold that of control glucose at both time points. FN protein also increased 1.5-fold that of control glucose at 48 hours. Anti-TGF-beta antibody completely abolished HG-induced FN synthesis. CONCLUSIONS: The present finding demonstrate that HG stimulates TGF-beta 1 very early and prior to FN production and that HG-induced FN production is mediated by TGF-beta. This finding is consistent with the view that TGF-beta mediates increased ECM accumulation by MC under high glucose conditions.
Animals↗
Demonstration that Australian Pasteurella multocida isolates from sporadic outbreaks of porcine pneumonia are non-toxigenic (toxA-) and display heterogeneous DNA restriction endonuclease profiles compared with toxigenic isolates from herds with progressive atrophic rhinitis.
Capsular types A and D of Pasteurella multocida cause economic losses in swine because of their association with progressive atrophic rhinitis (PAR) and enzootic pneumonia. There have been no studies comparing whole-cell DNA profiles of isolates associated with these two porcine respiratory diseases. Twenty-two isolates of P. multocida from diseased pigs in different geographic localities within Australia were characterised genotypically by restriction endonuclease analysis (REA) with the enzyme CfoI. Seven of 12 P. multocida isolates from nasal swabs from pigs in herds where PAR was either present or suspected displayed a capsular type D phenotype. These were shown to possess the toxA gene by polymerase chain reaction (PCR) and Southern hybridisation, and further substantiated by production of cytotoxin in vitro. The CfoI profile of one of these seven isolates, which was from the initial outbreak of PAR in Australia (in Western Australia, WA), was identical with profiles of all six other toxigenic isolates from sporadic episodes in New South Wales (NSW). The evidence suggests that the strain involved in the initial outbreak was responsible for the spread of PAR to the eastern states of Australia. Another 10 isolates, representing both capsular types A and D, were isolated exclusively from porcine lung lesions after sporadic outbreaks of enzootic pneumonia in NSW and WA. CfoI restriction endonuclease profiles of these isolates revealed considerable genomic heterogeneity. Furthermore, none of these possessed the toxA gene. This suggests that P. multocida strains with the toxA gene do not have a competitive survival advantage in the lower respiratory tract or that toxin production does not play a role in the pathology of pneumonic lesions, or both. REA with polyacrylamide gel electrophoresis and silver staining was found to be a practical and discriminatory tool for epidemiological tracing of P. multocida outbreaks associated with PAR or pneumonia in pigs.
Animals↗
A high glucose concentration stimulates the expression of monocyte chemotactic peptide 1 in human mesangial cells.
The mechanism of glomerular infiltration of monocytes remains unknown in diabetic nephropathy. We examined the effect of a high glucose concentration on monocyte chemotactic peptide 1 (MCP-1) expression in human mesangial cells (MCs) by using enzyme-linked immunosorbent assay and reverse transcription coupled with polymerase chain reaction (PCR). More than a 50% increase in the MCP-1 protein production was observed in MCs cultured in high-glucose medium (450 mg/dl) as compared to normal glucose (100 mg/dl; 1,496 +/- 75 vs. 966 +/- 15 pg/ml after 24 h, 1,910 +/- 93 vs. 1,250 +/- 55 pg/ml after 48 h). Semiquantitative PCR showed that phorbol myristate acetate (100 nM) increased the ratio of PCR products for MCP-1 to housekeeping gene glyceraldehyde-3-phosphate dehydrogenase on densitometric results at 24 h by 2.7-fold, which was prevented by calphostin C (200 nM) pretreatment. High glucose increased the ratio by 3-fold as compared to normal glucose at 24 h (0.72 +/- 0.11 vs. 0.24 +/- 0.01). This was also suppressed by calphostin C pretreatment. These findings demonstrate that high glucose can directly increase MCP-1 expression in MCs, which may contribute to monocyte infiltration in diabetic nephropathy, and this is regulated by protein kinase C.
Cells, Cultured↗
Modern medicine in Taiwan (II).
Taiwan's population has undergone rapid growth. From 3000000 in 1906. It had grown to 6000000 by 1941. By the end of 1996 the total population has reached 21500000. This large population is served by over 120000 health professionals. For every 10000 people there are 12.91 doctors (including 11.52 Western medical doctors and 1.39 Chinese medical doctors), 3.37 dentists and 9.36 pharmacists. There has been a huge change in causes of mortality. Under the Japanese occupation, the main causes of death were malaria, pneumonia, dysentery, enteritis, and pulmonary tuberculosis. After the return to Chinese control, the main causes were acute contagious diseases and digestive tract disease. At present, malignant tumors, cerebrovascular accident, heart disease, and diabetes are the main causes of death. With the development of the health-care system, infectious diseases have been controlled or eliminated. Malaria was eradicated from the island in 1956.
Cause of Death↗
Cloning and expression of a cDNA encoding a novel protein serine/threonine kinase predominantly expressed in hematopoietic cells.
We have isolated a cDNA clone of a new member of protein serine/threonine kinases, MPK38, from a cDNA library constructed from the murine teratocarcinoma PCC4 cell line by the polymerase chain reaction. MPK38 was transcribed as an approx. 2.5 kb mRNA encoding for a protein of 643 amino acids. N-terminus of MPK38 contains the kinase catalytic domain which exhibits approximately 60% protein sequence identity with the SNF1 serine/threonine kinase family. The MPK38 cDNA directs the in vitro translation of two protein species of approx. 70 and approx. 50 kDa, which appear to result from an internal initiation of translation. MPK38 was predominantly expressed in thymus and spleen, but was not detectable in kidney, liver, and muscle in the adult tissues. In addition, MPK38 was apparently expressed in T lineage cells and a macrophage/monocyte cell, but was not detectable in a B cell line and an embryonic cell line. However, a low level of MPK38 transcript was detectable in a mast cell line after a longer exposure. Furthermore, MPK38 gene product showed the kinase activity which was assessed by immune complex kinase assay. Thus, MPK38 gene product seems to play an important role in signal transduction of certain lineages of hematopoietic cells.
Amino Acid Sequence↗
Molecular cloning and chromosomal localization of a human gene homologous to the murine R-PTP-kappa, a receptor-type protein tyrosine phosphatase.
Tyrosine phosphorylation of proteins plays an important role in cellular signaling and many cellular activities. The levels of cellular phosphorylation are reversibly controlled by protein tyrosine kinases and protein tyrosine phosphatases. The murine R-PTP-kappa, a receptor-type protein tyrosine phosphatase, has recently been cloned (Jiang et al. (1993) Mol. Cell. Biol. 13, 2942-2951). In order to identify the protein tyrosine phosphatases critical to the cellular signal transduction in human keratinocytes, a polymerase chain reaction (PCR)-based strategy was employed, and we have cloned a human homologue of the murine R-PTP-kappa. Here, we report the isolation of a complementary DNA encoding a human R-PTP-kappa. Of the several overlapping cDNA clones, one clone, which we originally termed p55-7, was found to encode a transmembrane protein of 1440 amino acids and was highly conserved with murine R-PTP-kappa with 98% identity at the amino-acid levels. The human R-PTP-kappa gene was localized to chromosome 6 by southern hybridization of DNA from a rodent/human somatic cell mapping panel. Northern blot analysis of RNA from several human tissues revealed, like the murine R-PTP-kappa, the presence of a major mRNA of approx. 7.0 kb and a minor mRNA of approx. 5.3 kb. In contrast to the expression of murine R-PTP-kappa which was highly expressed in liver and kidney, the human R-PTP-kappa was predominantly expressed in spleen, prostate, and ovary. However, the transcripts were detectable at various levels in all examined tissues (thymus, testis, small intestine, and colon) except for PBL (peripheral blood leukocytes). In addition, human R-PTP-kappa displayed a restricted pattern of expression among a series of cell lines, and was apparently expressed in an epidermal cells and cell lines (human normal keratinocytes, HaCaT, and A431), but was not detectable in other cell lines tested after longer exposure.
Amino Acid Sequence↗
Tissue-specific protein-DNA interactions of the mouse protamine 2 gene promoter.
During spermiogenesis, the haploid phase of spermatogenesis, the genome is packaged into a highly compacted form and this process requires replacement of histones by protamines. In the mouse, protamines are encoded by two genes, which are transcriptionally regulated in testis. To understand the regulation of transcription of the mouse protamine 2 (mP2) gene, the tissue-distribution of sequence-specific interactions between nuclear proteins and promoter DNA sequences have been analyzed. Protein binding to the promoter region from -370 to +65 was studied using DNase I footprinting and gel shift assays. Five protein binding sites were identified, which are recognized by nuclear proteins from either testis or liver. Site 1 from -64 to -48, contains part of a cAMP responsive element (CRE), which in testis is recognized by CREM tau, an activator of post-meiotic transcription. Testicular protein(s) also binds to three other promoter domains: site 2, -87 to -67, a region containing a CAAT box, and sites 4 and 5, -239 to -210 and -328 to -311, sequences with similarity to consensus steroid hormone responsive elements (HRE). In contrast, interactions between the mP2 promoter and nuclear factors from liver, a tissue in which the mP2 gene is not transcribed, are observed at sites 1, 2, and 4, as well as at an additional region at site 3, -202 to -175. Because occupancy at site 3 appears to correlate with inactivation of the gene in non-testicular tissues, whereas testicular protein binding at site 5 appears to be associated with active transcription, we conclude that the mP2 promoter displays intricate tissue-specific patterns of protein/DNA interactions at key regulatory elements.
Animals↗
Effects of rebamipide in a model of experimental diabetes and on the synthesis of transforming growth factor-beta and fibronectin, and lipid peroxidation induced by high glucose in cultured mesangial cells.
Oxidative stress has been proposed as the basis for the pathogenesis of diabetic nephropathy. Rebamipide is a novel antiulcer drug that has, in addition, oxygen radical scavenging activity. Our study examines whether rebamipide could ameliorate the pathophysiology associated with experimental diabetes in vivo, such as microalbuminuria, and to reverse the increased production of transforming growth factor-beta1 and fibronectin in SV-40 transformed murine mesangial cells in culture that were stimulated with high glucose. Chronic administration of rebamipide (100 mg/kg/day, p.o., for 3 wk) to rats, in which diabetes was previously induced by the i.v. injection of streptozotocin 50 mg/kg, reversed hyperglycemia, which would contribute to prevent the increases in urinary excretion rates of albumin and lipid peroxides observed in this experimental model. Rebamipide, at this dose level, did not cause any discernible effect on age-matched control rats. Rebamipide 2 mM was as effective as 20 mM of dimethylthiourea, a known hydroxyl radical scavenger, in inhibiting the increase in lipid peroxides, transforming growth factor-beta1, fibronectin mRNAs and proteins induced by incubation of cultured mesangial cells with high glucose. Our data suggest that rebamipide attenuates high glucose-induced nephropathy, which is attributable, in part, to its antioxidative property and, in part, to its effect on reversing hyperglycemia.
Alanine↗
Role of glycated low density lipoprotein in mesangial extracellular matrix synthesis.
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Animals↗
Transforming growth factor-beta1 inhibits human keratinocyte proliferation by upregulation of a receptor-type tyrosine phosphatase R-PTP-kappa gene expression.
We studied regulation of a receptor-type tyrosine phosphatase R-PTP-kappa gene expression in a human keratinocyte cell line, HaCaT. Addition of TGF-beta 1 to the HaCaT cells markedly induced the expression of R-PTP-kappa mRNA in a time- and dose-dependent manner. The induction of R-PTP-kappa mRNA expression was observed at a dose as low as 0.02 ng/ml TGF-beta1 and reached a peak at 2 ng/ml TGF-beta 1 after 6 h treatment. The TGF-beta 1-induced R-PTP-kappa mRNA expression was suppressed by sodium orthovanadate, a tyrosine phosphatase inhibitor, and H7, a serine/threonine kinase inhibitor, but not by genistein, a tyrosine kinase inhibitor. In addition, the inducing effect is not dependent on de novo protein synthesis. Taken together, these results suggest that TGF-beta 1 inhibits the human keratinocyte proliferation in vitro, possibly through induction of R-PTP-kappa gene expression.
Cell Division↗