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Biomedical subjects

R Kikkawa

Publications and source records attributed to R Kikkawa.

210 records · Page 12Linked to original sources
PubMedDate not supplied

Glucose-induced overproduction of type IV collagen in cultured glomerular mesangial cells.

Type IV collagen production by cultured rat glomerular mesangial cells was evaluated quantitatively by measuring type IV collagen secreted into culture media and associated with the cells using enzyme-linked immunosorbent assay (ELISA). The majority of type IV collagen was secreted into culture media; type IV collagen increased with cell growth in the early log phase and decreased in the late log phase and after cofluency. By exposing the cells to high concentrations of glucose (27.8 mM), both secreted and cell-associated type IV collagens increased significantly compared with the cells cultured under normal glucose concentrations (5.6 mM) or under equivalent concentrations of mannitol, resulting in a significant increase in total type IV collagen accumulation.

Animals↗
PubMedDate not supplied

Reduced activity of renal angiotensin-converting enzyme in streptozotocin-induced diabetic rats.

To clarify the possible role of intrarenal renin-angiotensin system (RAS) in the evolution of renal hemodynamic alteration in diabetes, we investigated the change of tissue angiotensin-converting enzyme (ACE) activity, a key enzyme of RAS, in the kidneys obtained from streptozotocin-induced diabetic rats. Tissue ACE activity was significantly reduced in both outer cortex (0.29 +/- 0.04, mean +/- SEM, n = 6) and inner cortex with outer medulla (2.43 +/- 0.28, n = 6) of the kidneys from diabetic rats 2 weeks after induction of diabetes compared with those from control rats (0.47 +/- 0.05, n = 7, in outer cortex; 3.68 +/- 0.32, n = 7, in inner cortex with outer medulla). ACE activities in the lung and aorta of diabetic rats were not different from those of control rats. ACE activities in the serum and urine were significantly elevated in diabetic rats. Treatment of diabetic rats with insulin to achieve near euglycemia completely prevented these alterations in ACE activity, except that, in the urine, the elevation of ACE was partially corrected with insulin. In contrast to ACE activity, activity of N-acetyl-beta-D-glucosaminidase (a lysosomal enzyme of the tubule) and r-glutamyl transpeptidase (a brush border enzyme) in the kidney were not reduced in diabetic rats, whereas in the urine both enzyme activities were significantly elevated in diabetic rats. It is likely, therefore, that the reduction of ACE activity in the kidneys of diabetic rats may reflect the impairment of vascular endothelial cells in the kidney, rather than tubular damage.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylglucosaminidase↗
PubMedDate not supplied

High blood pressure is a risk factor for the development of microalbuminuria in Japanese subjects with non-insulin-dependent diabetes mellitus.

In this study, 52 nonproteinuric Japanese patients with non-insulin-dependent diabetes (NIDDM) were followed from 1985 to 1990 to investigate the rate of development and progression of microalbuminuria and the factors which influence it. In 1985, 34 patients were normoalbuminuric, and 18 patients were microalbuminuric. Five years later, 11 of 34 initially normoalbuminuric patients (32.4%) developed microalbuminuria, and 6 of 18 initially microalbuminuric patients (33.3%) developed overt proteinuria. At the beginning of the study, hypertension existed more frequently in the patients who later developed microalbuminuria (8 of 11, 72.7%) than in the patients who stayed normoalbuminuric (4 of 23, 17.4%). Age-adjusted values of mean blood pressure (+/- SEM) at the beginning of the study in the patients who developed microalbuminuria (98.2 +/- 3.4 mm Hg, n = 11) were significantly higher than those in the patients who stayed normoalbuminuric (87.3 +/- 2.4 mm Hg, n = 23). In six patients who developed overt proteinuria, initial urinary albumin excretion rates (AER) were higher than those in the patients who stayed microalbuminuric, and four patients who presented with initial AER greater than 100 micrograms/min all developed overt proteinuria. These results indicate that, in Japanese patients with NIDDM, the rate of development of microalbuminuria is faster than that reported in Caucasian IDDM, and preexisting hypertension with relatively poor control of blood pressure may be a risk factor for the development of microalbuminuria.

Adult↗
PubMedDate not supplied

Significance of fructose-induced protein oxidation and formation of advanced glycation end product.

To investigate the significance of fructose-induced protein modification, we examined both fructose- and glucose-induced protein oxidation and the formation of advanced glycation end products (AGE) in vitro. Albumin incubated in the presence of 100 mM fructose at 37 degrees C for 1 week showed 5.1-fold and 3.1-fold increases in the content of carbonyl, which is a marker for oxidized protein, when compared with either control incubated without sugar or with 100 mM glucose. Similarly, the same incubation with fructose increased the fluorescence intensity over 100-fold and 15-fold formation compared with that of no sugar and glucose controls, respectively. Both fructose-induced fluorescence and protein oxidation were almost completely suppressed in the presence of the iron chelator; deferoxamine (100 microM), the hydroxyl radical scavenger; MK-447 (1 mM), or aminoguanidine (200 mM), which is an inhibitor of AGE formation. In contrast, the fructose-induced formation of fluorescent albumin was potentiated in the presence of 100 microM FeCl2. This was completely inhibited in the presence of 60 microM or more deferoxamine. These results suggest that fructose promotes both AGE formation and protein oxidation possibly through the formation of hydroxyl radicals.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMedDate not supplied

Abnormalities in protein kinase C and MAP kinase cascade in mesangial cells cultured under high glucose conditions.

In order to clarify the mechanism of mesangial cell dysfunction in diabetes, we examined the activities of protein kinase C (PKC) and mitogen-activated protein kinase (MAPK), important kinases in various cellular functions, and also evaluated the isoenzymes of PKC in mesangial cells cultured under high glucose conditions. Exposure of cells to high concentrations (27.8 mM) of glucose for 5 days resulted in a significant elevation of PKC activities in the membrane fraction. MAPK was also activated in cells cultured under high glucose conditions. Of the PKC isoenzymes, the levels of PKC alpha and zeta were significantly increased in the membrane fraction after 5 days of exposure to high concentrations of glucose. These results indicate that the translocation of PKC alpha and zeta and the activation of MAPK under high glucose conditions might be underlying mechanisms of the functional disturbance of mesangial cells in diabetes.

Animals↗
PubMedDate not supplied

Cyclic nucleotides attenuate endothelin-1-induced activation of mitogen-activated protein kinase in cultured rat mesangial cells.

In order to clarify the mechanisms of interaction between endothelin-1 (ET-1) and cyclic AMP (cAMP) or cyclic GMP (cGMP), we examined the effects of cAMP or cGMP on ET-1-induced activation of mitogen-activated protein kinase (MAPK), one of the key enzymes in the signal transduction of ET-1, in cultured rat mesangial cells. ET-1 was able to activate both p42 and p44 MAP kinases in a dose-dependent manner. Cell permeable analogues of cAMP and cGMP, dibutylyl cAMP (BT2-cAMP) and 8 bromo cGMP (8br-GMP), significantly inhibited ET-1-induced activation of MAPK. Atrial natriuretic peptide (ANP), which increased cellular cGMP, was able to inhibit ET-1-induced activation of MAPK in a dose-dependent manner, while c-ANP, an analogue specific to the clearance receptors of ANP, exerted no effect. These results indicate that cAMP and cGMP could modulate the action of ET-1 in mesangial cells at a step of the activation of MAPK.

Animals↗
PubMedDate not supplied

Microalbuminuria cannot predict cardiovascular death in Japanese subjects with non-insulin-dependent diabetes mellitus.

In order to examine whether the existence of microalbuminuria can predict the development of overt proteinuria and cardiovascular death in Japanese subjects with non-insulin-dependent diabetes mellitus (NIDDM), we investigated 47 patients for a 10-year follow-up period. Patients were divided into two groups by the initial values of urinary albumin excretion rates. The percentage of patients who developed overt proteinuria during the follow-up period was significantly higher in patients who were initially classified as microalbuminuric group (63.6%) than in normoalbuminuric group (17.4%). During the follow-up period, one of the patients with normoalbuminuria had died of congestive heart failure, while four of those with microalbuminuria had died; one of stroke and three from noncardiovascular diseases. These results indicate that the existence of microalbuminuria had the predictive power for the development of overt proteinuria, but not for cardiovascular death in Japanese subjects with NIDDM.

Albuminuria↗
PubMedDate not supplied

Clinical investigation of epalrestat, an aldose reductase inhibitor, on diabetic neuropathy in Japan: multicenter study. Diabetic Neuropathy Study Group in Japan.

A number of diabetic patients with diabetic neuropathy were treated with epalrestat, an aldose reductase inhibitor, since this drug was launched into the market in Japan. More than 5000 patients with diabetic neuropathy who were treated with epalrestat for 3-12 months were treated to analyze the efficacy and the adverse reactions of the drug in this study. The improvement rates of subjective symptoms (i.e., spontaneous pain, numbness, coldness, and hypoesthesia) was 75% (slightly improved or better) and those of nerve function tests (i.e., motor nerve conduction velocity, sensory nerve-conduction velocity, and vibration threshold) 36%. Adverse drug reactions were encountered in 129 cases (2.5%) out of 5249 patients, none of which were severe ones. Although data are limited, they strongly suggest that epalrestat is a highly effective and safe agent for the treatment of diabetic neuropathy.

Adult↗
PubMedDate not supplied

Significance of glomerular deposition of C3c and C3d in IgA nephropathy.

BACKGROUND: Complement activation plays an important role in the pathogenesis of IgA nephropathy. The clinico-pathological significance of the glomerular deposition of complement breakdown products, C3c and C3d in IgA nephropathy remains to be clarified. METHODS: We examined the relationship between glomerular staining patterns of C3c and C3d and clinico-pathological findings with 163 patients with IgA nephropathy. Renal biopsy specimens were stained with C3c and C3d by immunofluorescence, and patients were divided into the following two groups: the intensity of C3c deposition stronger than C3d deposition, or equal to it (group A); the intensity of C3d deposition stronger than C3c deposition (group B). RESULTS: In group A, the incidence of severe hematuria (over 20 urinary red blood cells in high-power field microscope (x400)) or of higher urinary fibrinogen degenerated products (over 0.1 microg/ml) was significantly higher than that in group B. In addition, group A showed a significant decrease in the glomerular filtration rate. Group A also showed a significantly higher incidence of glomerular endocapillary proliferation than in group B. CONCLUSION: These findings suggest that the glomerular deposition of C3c is associated with the inflammatory active phase of glomeruli in IgA nephropathy.

Adolescent↗
PubMedDate not supplied

A role of mesangial dysfunction in the development of diabetic nephropathy.

The pathogenic mechanism of diabetic nephropathy has been extensively investigated, and the significance of alteration in glomerular hemodynamics or mesangial cell metabolism has been recently clarified. It is expected that in the near future these pathologically important alterations can be corrected, and the development diabetic nephropathy can be halted.

Animals↗
PubMedDate not supplied

Concerted regulation of early enterocyte differentiation by insulin-like growth factor I, insulin, and transforming growth factor-beta1.

To clarify the roles of insulin on the proliferation and differentiation of intestinal epithelial cells (IECs), we examined the effect of insulin-like growth factor-I (IGF-I) and insulin for the growth and differentiation of IEC-6 cells, a crypt cell line derived from rat small intestine. IGF-I (100 nM) stimulated the proliferation of IEC-6 cells, and insulin (1-100 nM) antagonized the IGF-I effect and caused the cells' G1-arrest, resulting in differentiated characteristics of IECs, such as increased general protein synthesis and the formation of microvilli. To clarify the mechanisms of these phenomena, cell surface [125I]insulin binding and the content of immunoreactive insulin receptors were analyzed by Western blotting. Insulin receptors transiently appeared on the cell surface during the early G1 phase after the IGF-I stimulation. Under those conditions, the concomitant presence of insulin stimulated the appearance of active transforming growth factor-beta1 (TGF-beta1) in the media, and then TGF-beta1 antagonized the IGF-I-induced cell proliferation. Such a TGF-beta1 effect was blunted by a neutralizing antibody against TGF-beta1, indicating that the insulin effect was in part mediated through the autocrine-paracrine secretion of TGF-beta1. These results suggest that the regulation of the proliferation of IECs are an early step in those cells' differentiation that may accompany hormonal changes during nutrient intake and may be caused by the sequential effects of IGF-I, insulin, and TGF-beta1.

Animals↗