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Biomedical subjects

R Kikkawa

Publications and source records attributed to R Kikkawa.

At least 19 recordsLinked to original sources
PubMed1992

Increased plasma post-heparin diamine oxidase activity and plant sterol levels in streptozotocin diabetic rat.

Plasma post-heparin diamine oxidase (DAO) activity and plasma levels of plant sterols were examined in streptozotocin diabetic rats fed with chow containing plant sterols, to investigate the enzyme activity in relation to the morphological changes of small intestine as well as sterol absorption in the diabetic rats. Diabetic rats showed increased small intestinal mass and surface area compared with control rats. Plasma post-heparin DAO activity and plant sterol level were also increased more than 2.5-fold in the diabetic rats. Insulin treatment improved these abnormalities. Plasma DAO activity correlated to both the small intestinal hyperplastic change and plasma plant sterol levels. These results indicate that plasma post-heparin DAO activity may be used as a marker of intestinal hypertrophy as well as ability to absorb dietary sterols.

Amine Oxidase (Copper-Containing)↗
PubMed1992

A combination of the aldose reductase inhibitor, statil, and the prostaglandin E1 analogue, OP1206.alpha CD, completely improves sciatic motor nerve conduction velocity in streptozocin-induced chronically diabetic rats.

In view of the possible implication of multifactorial mechanisms in the pathogenesis of diabetic neuropathy, the aldose reductase inhibitor (ARI), Statil, which ameliorates abnormal sorbitol or myo-inositol metabolism in diabetic nerves, and the prostaglandin E1 (PGE1) analogue, OP1206.alpha CD (OP), which improves diabetic vascular derangements, were administered simultaneously for 2 months to streptozocin (STZ)-induced diabetic rats with 5 months' duration of diabetes, and the effects on sciatic motor nerve conduction velocity (MNCV), Na(+)-K(+)-adenosine triphosphatase (ATPase) activity, and morphology of myelinated nerve fibers (MNF) were compared with the effects of a monotherapy with OP. The combination regimen ameliorated abnormal nerve sorbitol and myo-inositol levels and normalized decreased MNCV and enzyme activity. In contrast, neither sorbitol nor myo-inositol metabolism was ameliorated, and only insufficient improvement of MNCV and morphology of MNF was obtained with a monotherapy with OP. In addition, the combination therapy reversed both a decrease in the percent of large MNF and an increase in the percent of small MNF in diabetic rats, whereas a monotherapy with OP reversed only a decrease in the percent of large MNF. The results might suggest that a multiple-drug therapy with different mechanisms of action has greater effects on diabetic neuropathy than a single-drug therapy and is worthy of clinical consideration.

Aldehyde Reductase↗
PubMed1992

Hypertension and the development of complications in patients with non-insulin dependent diabetes mellitus in Japan.

Hypertension is a very frequent condition in individuals with non-insulin dependent diabetes mellitus (NIDDM) in Japan and has affected the occurrence of late diabetic complications, especially stroke and nephropathy. Despite similar characteristics of hypertension among Japanese and white patients, the effect of hypertension on the development of coronary artery disease (CAD) in these two populations is strikingly different. In white NIDDM patients, hypertension is one of the major risk factors for the development of CAD. However, CAD is an infrequent complication in NIDDM patients in Japan, even though they have hypertension, lipid abnormalities, and renal complications.

Adult↗
PubMed1992

Familial spinal xanthomatosis with sitosterolemia.

A family with multiple spinal xanthomas and sitosterolemia is described. A 48-year-old woman presented with paraplegia due to multiple intradural extramedullary tumors. The patient also showed marked tendon xanthomas and analysis of sterol composition in both plasma and the xanthoma established the diagnosis of the rare inherited metabolic disease, sitosterolemia and xanthomatosis. Two other siblings in the family presented with marked tendon xanthomas and coronary atherosclerosis, but did not show any neurological signs or symptoms. Magnetic resonance imaging (MRI) study revealed multiple intradural extramedullary tumors in spinal canals of the proband and her sister, but not in the other affected sibling (brother). This is the first report of familial occurrence of multiple extramedullary spinal tumors due to the inherited metabolic abnormality.

Cholesterol↗
PubMed1992

Identification and characterization of aldose reductase in cultured rat mesangial cells.

Although the enhanced activity of the polyol pathway has been detected in diabetic glomeruli, the intraglomerular localization of this pathway has not yet been well defined. In this study, we attempted to identify aldose reductase, a key enzyme of the polyol pathway, in cultured rat mesangial cells and to characterize the properties of this enzyme using enzymological and immunological methods. When the aldose reductase (DL-glyceraldehyde-reducing) activity was analyzed in mesangial cell extract, the Lineweaver-Burk plot showed concave downward curvature, and the Michaelis constant was 0.83 mM DL-glyceraldehyde, and this activity was noncompetitively inhibited by an aldose reductase inhibitor, ICI-128,436. The enzyme activity was enhanced by the addition of sulfate ion and partially suppressed by barbital. The enzyme cross-reacted with the antisera against rat lens and testis aldose reductases on Ouchterlony plate, and migrated to the region of molecular weight of about 36,500 Da on Western blotting. The presence of aldose reductase mRNA was also confirmed by Northern analysis using cDNA for rat aldose reductase, 10Q. From these results, it was concluded that the aldose reductase may exist in rat glomerular mesangial cells and may play a role in the development of diabetic glomerulopathy, though the coexistence of aldehyde reductase(s) may not be fully ruled out.

Aldehyde Reductase↗
PubMed1992

[A study of the measurement of p-aminohippurate in diabetic subjects].

Glomerular filtration rate has been found to be elevated in the early stage of insulin-dependent diabetes mellitus and has been proposed to play a pathogenetic role in the development of diabetic nephropathy. However, the reports about the change in renal plasma flow (RPF) among diabetic subjects were inconsistent, suggesting that the presence of hyperglycemia may in some way interfere the procedures of RPF measurement. Recently, it has been reported that the glucose in the urine may react with p-aminohippurate (PAH), a widely used marker for RPF measurement, and influence the chemical measurement of PAH, misleading the result of RPF value. In fact, we obtained the decrease of PAH value in urine samples obtained from diabetic subjects during the storage for one week in frozen condition. In order to clarify the factors which may influence the glucose-PAH reaction, we have conducted various in vitro studies. The decrease of PAH values was dose-dependent to urine glucose. The pH of the test solution or urine was also found to greatly influence the result of PAH measurement when glucose was present. The analysis of glucose-PAH reactants by HPLC suggested that the amino residue of PAH might be reacted with glucose, producing the glycation product (Schiff base). The rate of glycation of PAH was time- and pH-dependent. However, when the reaction time was prolonged at the last step of PAH measurement after the addition of the acid solution, the decrease of PAH value was gradually corrected reaching to the theoretical value in 7 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Acids↗
PubMed1992

[Abnormality of type IV collagen metabolism in the development of diabetic nephropathy].

Diabetic nephropathy is characterized by the thickening of glomerular basement membrane and the expansion of mesangium. These changes are considered to be caused by an accumulation of the extracellular matrix protein including type IV collagen. The mesangial cells are the cells responsible for the synthesis and metabolism of type IV in the mesangial cells are discussed. The role of advanced glycation end products in the pathogenesis of diabetic nephropathy will be also discussed.

Collagen↗
PubMed1992

[Measurement of renal plasma flow and glomerular filtration rates in diabetic subjects].

To clarify the problem in the measurement of renal plasma flow and glomerular filtration rates in diabetes, the effect of glucose on the determination of para-aminohippuric acid (PAH) and inulin was examined. The concentration of urinary PAH in glucosuric diabetic subjects decreased after the storage of urine samples because of the glycation of PAH. Therefore, glucose must be removed by the acid treatment before the determination of the concentrations of urinary PAH. Since glucose can interfere with the assay of inulin, the sample must be treated with NaOH prior to the determination of the inulin concentration. GFR of the subjects with type 2 diabetes was next examined. GFR in the subjects with a duration of diabetes less than 10 years was significantly higher than that in the subjects with a duration of diabetes more than 10 years. Thus, the subjects with short-term type 2 diabetes may present with hyperfiltration similar to the subjects with short-term type 1 diabetes.

Diabetes Mellitus, Type 2↗
PubMed1991

Glucose enhances type IV collagen production in cultured rat glomerular mesangial cells.

Type IV collagen production by cultured glomerular mesangial cells and the effect of glucose on it were evaluated in order to explore the possible contribution of mesangial cells to the accumulation of type IV collagen in mesangial matrix typically seen in diabetes. Type IV collagen was measured quantitatively by enzyme-linked immuno-sorbent assay. The majority of type IV collagen was secreted into culture media and secreted-type IV collagen increased with cell growth in early log phase and decreased in late log phase and after confluency. By exposing the cells to high concentrations of glucose (27.8 mmol/l), both secreted- and cell-associated-type IV collagens increased significantly compared with the cells cultured under normal glucose concentrations (5.6 mmol/l) or under equivalent concentrations of mannitol, resulting in a significant increase in total type IV collagen accumulation from 32.1 +/- 6.4 (under 5.6 mmol/l glucose) to 51.0 +/- 4.6 micrograms/dish (mean +/- SD, n = 4) on day 4, from 113.6 +/- 6.6 to 156.8 +/- 7.1 on day 6, from 248.5 +/- 15.2 to 310.0 +/- 12.6 on day 8 and from 372.4 +/- 14.8 to 507.9 +/- 17.2 on day 12. These results indicate the importance of glucose-induced alteration of mesangial cell function in the development of diabetic mesangial expansion.

Animals↗
PubMed1991

Metabolic actions of insulin-like growth factor I in cultured glomerular mesangial cells.

Glomerular mesangial cells in culture have been reported to possess a considerable number of receptors specific to insulin-like growth factor I (IGF-I), with very small number of receptors specific to insulin. To explore acute metabolic effects of IGF-I on mesangial cells, uptake of glucose and amino acid was measured in the presence of IGF-I or insulin. IGF-I stimulated D-[U-14C]glucose incorporation, 2-deoxy[1-3H]glucose uptake and alpha-[methyl-3H]aminoisobutyric acid (AIB) uptake into cultured mesangial cells by 139.8% +/- 2.1%, 116.6% +/- 1.7%, and 214.9% +/- 12.8% (percent of basal), respectively. Similar maximal stimulation was also induced by insulin, while the ED50 of IGF-I to stimulate these uptake systems (9.98 +/- 2.36, 3.45 +/- 1.86, and 3.35 +/- 0.40 ng/mL, respectively) was significantly lower than that of insulin (120.8 +/- 28.5, 61.8 +/- 7.7, and 76.3 +/- 17.5, respectively). These results indicate that, in cultured glomerular mesangial cells, IGF-I induces acute metabolic effects, possibly through its own receptors.

Amino Acids↗
PubMed1991

Dual mechanism of angiotensin II inhibits ANP-induced mesangial cGMP accumulation.

To evaluate an interaction between vasoconstrictive (Ang II) and vasodilating (ANP) peptides, we examined the effect of Ang II on ANP-induced accumulation of cGMP in cultured glomerular mesangial cells. ANP rapidly increased intracellular cGMP levels, with a peak stimulation at one minute in the absence of IBMX and at ten minutes in the presence of IBMX. The ANP-induced cGMP accumulation was significantly inhibited when the cells were treated with Ang II simultaneously with ANP for one minute in the absence of IBMX. This inhibitory effect of Ang II was completely abolished by IBMX and significantly reduced in calcium-free media or by W7, but not affected by H7. Similar inhibitory effect was observed when cells were treated with A23187 but not with TPA for one minute. In the presence of IBMX, Ang II inhibited ANP-induced cGMP accumulation when cells were treated with Ang II for 15 minutes prior to the stimulation by ANP. This inhibition by Ang II was blocked by H7. ANP-induced increase in particulate guanylate cyclase activity was significantly reduced in the cells treated with Ang II or TPA. This reduction of enzyme activity was also prevented by H7. These results indicate that Ang II inhibits ANP-induced cGMP accumulation in cultured glomerular mesangial cells through at least two mechanisms; one is the activation of calcium-dependent, calmodulin-stimulated cyclic nucleotide phosphodiesterase in the initial phase, and the other is the inhibition of guanylate cyclase resulting from protein kinase C activation in the maintenance phase.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1991

Amelioration of nerve Na(+)-K(+)-ATPase activity independently of myo-inositol level by PGE1 analogue OP-1206.alpha-CD in streptozocin-induced diabetic rats.

An oral prostaglandin E1 (PGE1) analogue, OP-1206.alpha-CD, was given to rats with streptozocin (STZ)-induced diabetes to examine the therapeutic effects of OP-1206 on short-term and long-term diabetic neuropathy and its action mechanism with special reference to nerve Na(+)-K(+)-ATPase activity. In the short-term experiment, OP-1206 was administered daily to diabetic rats in 3- and 30-mg/kg doses for 4 wk from the day of STZ injection. In the long-term study, 10 micrograms/kg OP-1206 was also given daily for 8 wk from 7 mo after induction of diabetes. The compound improved decreased sciatic motor nerve conduction velocity in both short-term and long-term diabetic rats. The nerve Na(+)-K(+)-ATPase activity of diabetic rats, reduced by 40% compared with controls, was reversed to the level of controls in both experiments, whereas weight loss and hyperglycemia were unchanged, and neither nerve sorbitol accumulation nor myo-inositol depletion was corrected. In a morphometric analysis of myelinated nerve fibers (MNFs) in long-term diabetes, the mean diameter of the largest 10% of MNFs was significantly reduced in untreated diabetic compared with control rats, but OP-1206 completely reversed this reduction. The results suggest that OP-1206 ameliorates a decrease in nerve Na(+)-K(+)-ATPase activity without any effect on nerve myo-inositol level and that the compound may be not only a potent therapeutic agent for the treatment of diabetic neuropathy but also a useful research tool to investigate the mechanism of nerve Na(+)-K(+)-ATPase activity regulation.

Alprostadil↗
PubMed1991

Effect of dietary protein restriction on proteinuria in non-insulin-dependent diabetic patients with nephropathy.

To determine the effectiveness of dietary protein restriction on proteinuria in patients with non-insulin dependent diabetes (NIDDM), 14 diabetic patients with overt nephropathy were placed on either a low protein diet (N = 7) or conventional protein diet (N = 7) for one month. After the study period, daily urinary protein excretion rates decreased significantly, from 3.2 +/- 0.4 to 1.9 +/- 0.4 g/day, and serum albumin levels increased from 3.3 +/- 0.2 to 3.7 +/- 0.5 g/dl only in the low protein diet group, without any significant changes in either serum creatinine levels or creatinine clearance. These findings suggest that dietary protein restriction has a beneficial role in the treatment of NIDDM patients with overt nephropathy.

Adult↗
PubMed1991

[Metabolic and mitogenic effects of insulin-like growth factor I on rat glomerular mesangial cells cultured under high concentration of glucose].

Recent studies indicate the important roles of mesangial cell dysfunction and insulin-like growth factor I (IGF-I) in the development of diabetic nephropathy. In order to know whether hyperglycemia could alter IGF-I action on mesangial cells, we examined mitogenic and metabolic effects of IGF-I on mesangial cells. Mesangial cells revealed to express considerable numbers of receptors specific to IGF-I will relatively small numbers of insulin receptors. The uptake of [3H]-2-deoxy-glucose, [3H]-aminoisobutyric acid (AIB), or [3H]-thymidine into mesangial cells was stimulated by IGF-I at physiological concentrations. Under high concentrations of glucose (55 mM), the stimulation of thymidine uptake by IGF-I was significantly suppressed from 5863 +/- 549 (at 11 mM glucose) to 1731 +/- 146 DPM/100 micrograms/prot. On the contrary, AIB incorporation by IGF-I was significantly enhanced in the cells cultured under high concentration of glucose, as 2.03 +/- 0.03n mol/mg protein/15 min at 55 mM glucose vs 0.59 +/- 0.01 at 11 mM glucose. In conclusion; 1) IGF-I had metabolic and mitogenic effects on rat mesangial cells at physiological concentrations. 2) under excess glucose conditions, mitogenic action of IGF-I on rat mesangial cells was suppressed, while amino acid incorporation was enhanced. These results suggest that modulation of IGF-I effects on mesangial cell by glucose could be associated with mesangial cell dysfunction in diabetes.

Aminoisobutyric Acids↗
PubMed1990

Glucose inhibits myo-inositol uptake and reduces myo-inositol content in cultured rat glomerular mesangial cells.

Although activation of polyol pathway has been proposed as one of the etiologic factors of diabetic complications, precise mechanism of the effect of polyol accumulation is still unclear. In order to test the hypothesis that there is an association of polyol pathway with myo-inositol metabolism, we measured myo-inositol content in cultured rat glomerular mesangial cells. By exposing the cells to high concentrations of glucose, intracellular myo-inositol content was reduced from 12.39 +/- 0.64 nmol/mg protein at 0 mmol/L glucose to 6.54 +/- 0.38 nmol/mg protein at 27.5 mmol/L glucose and 4.88 +/- 0.43 nmol/mg protein at 55 mmol/L glucose. This decrease of myo-inositol content was partially prevented by co-incubation with aldose reductase inhibitor, sorbinil. To examine further the mechanism of myo-inositol depletion, myo-inositol uptake by mesangial cells was studied. Major myo-inositol uptake process was sodium-dependent, saturable, and ouabain sensitive with Vmax of 171 pmol/mg protein/20 min and Km of 33 mumol/L. Sodium-dependent myo-inositol uptake was significantly inhibited by glucose in a dose-dependent manner only when glucose was present during uptake experiment, and kinetic analysis revealed the inhibition was competitive. Aldose reductase inhibition failed to prevent inhibitory effect of glucose on myo-inositol uptake. These data suggest that myo-inositol content of glomerular mesangial cells, which is reduced by high concentrations of glucose, is maintained by two processes: a glucose-sensitive but sorbitol-insensitive process, sodium-dependent myo-inositol uptake; and a sorbitol (aldose reductase) sensitive process, myo-Inositol depletion under high glucose condition may induce dysfunction of mesangial cells seen in diabetes.

Aldehyde Reductase↗
PubMed1989

Chronically streptozocin-diabetic monkey does not closely mimic human diabetic neuropathy.

In order to evaluate the value of diabetic Japanese monkeys (Macaca fuscatus) as an animal model for studying the pathogenesis of diabetic neuropathy, morphological examinations were performed on myelinated nerve fibers and endoneurial microvessels at three levels of the lower limb nerve in eight streptozocin (STZ)-diabetic monkeys with the duration of diabetes up to 36 months and in four roughly age-matched control monkeys using a computer-assisted image analyzer. Nerve fiber loss was not found, although a tendency for nerve fiber atrophy was found in diabetic monkeys. Endoneurial microvessels did not show either endothelial or pericyte proliferation or basement membrane thickening. The results suggest that chronically STZ-diabetic Japanese monkeys with the duration of diabetes up to 36 months might be useful for studying diabetic axonopathy, but do not closely mimic the nerve pathology found in human diabetic neuropathy.

Animals↗