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J H Kinoshita

Publications and source records attributed to J H Kinoshita.

At least 19 recordsLinked to original sources
PubMed1992

The efficacy of aldose reductase inhibitors on polyol accumulation in human lens and retinal pigment epithelium in tissue culture.

The formation of excess sugar alcohol mediated by aldose reductase (AR) and its intracellular accumulation in lens with resultant hydration is thought to be the initiating mechanism in the pathogenesis of diabetic and galactosemic cataracts. AR is also involved in other diabetic complications including retinopathy and neuropathy. Therefore, there is heightened interest in developing effective AR inhibitors (ARIs) for possible clinical use in human diabetes. However, the evaluation of these drugs for potential clinical use requires that the compounds be evaluated in appropriate target tissues since AR from different tissues is known to exhibit differential susceptibility to ARIs. The relative efficacy of ARIs in human lens epithelium (HLE) and human retinal pigment epithelium (HRPE) was studied by measuring the degree of inhibition of galactitol formation at various concentrations of ARI following incubation of cells in high galactose media for 72 hrs. Regardless of the structural characteristics of the ARIs investigated, higher doses were required to inhibit polyol synthesis in HRPE as compared to HLE cells. Based on ED50 values, dose required for 50% inhibition, the order of potencies against both HLE and HRPE enzymes was AL-4114 greater than AL-3152 greater than AL-1576 greater than tolrestat greater than statil greater than sorbinil. Since some ARIs are known to be bound to plasma proteins, it is conceivable that the observed differences in ED50 values could be due to differential binding to serum proteins in the culture medium. This possibility was examined by employing cultures of dog lens epithelium (DLE). These cells, which synthesize much higher levels of galactitol than HLE and HRPE, could be maintained in serum-free media for short periods (4 hrs) of time. The results, which demonstrate that the extent of polyol inhibition was the same in the presence or absence of serum, suggest that the differences in the potency of the inhibitors may reflect their inherent activity against AR in HLE and HRPE cells.

Adult↗
PubMed1991

Polyol accumulation in cultured human lens epithelial cells.

Human lens epithelial (HLE) cells in tissue culture accumulated significant levels of galactitol when they were cultured for 72 hr in medium containing 30 mM D-galactose. Polyol accumulation was accompanied by the appearance of vacuoles as seen by transmission electron microscopy. The number and size of intracellular vacuoles increased when the culture period was extended to 7 days. In addition, polyol accumulation was accompanied by loss of myoinositol. None of these changes occurred in cells exposed to 30 M L-galactose which is not a substrate for aldose reductase. The accumulation of galactitol, intracellular vacuole formation and loss of myoinositol observed in D-galactose-exposed cells were prevented by the inclusion of the aldose reductase inhibitor, sorbinil, in the culture medium. Comparison of the relative efficacies of two aldose reductase inhibitors indicate that AL 1576 is nearly 20 times more potent than sorbinil in inhibiting the human lens enzyme. It is concluded that vacuole formation in HLE cells is due to the osmotic effect of polyol formation brought about by the action of aldose reductase and that the etiology of human diabetic cataract may also involve the polyol pathway.

Aldehyde Reductase↗
PubMed1990

Prevention of retinal vessel changes associated with diabetic retinopathy in galactose-fed dogs by aldose reductase inhibitors.

Vascular changes associated with early diabetic retinopathy that include the selective degeneration of pericytes, the formation of microaneurysms and acellular capillaries, and vessel dilation have been experimentally investigated in age- and sex-matched beagle dogs fed a 30% galactose diet and treated with or without the aldose reductase inhibitors sorbinil and/or M79175. Eyes from dogs in each group were periodically enucleated during a 36-month period and their retinal capillaries were examined as trypsin-digested flat preparations. These studies reveal that the destruction of retinal pericytes to form pericyte ghosts is the earliest observable retinal vessel change occurring after 19 to 21 months of galactose feeding. By 24 months, both an irregular distribution of endothelial cell nuclei near pericyte ghosts and the presence of acellular capillaries containing neither endothelial cells nor pericytes can be observed. This was followed by the histologic appearance of microaneurysms after 27 months and the funduscopic appearance of intraretinal hemorrhages after 33 months. Varicose enlargements of capillaries were also observed in the trypsin-digested preparations from dogs fed galactose for 33 to 36 months. All of these changes are linked to the initial aldose reductase-associated destruction of pericytes. The onset and progression of these retinal changes were retarded in a dose-dependent manner with aldose reductase inhibitors.

Aldehyde Reductase↗
PubMed1990

A thirty year journey in the polyol pathway.

The development of the concept that aldose reductase (AR) is involved in diabetic complications is presented from its early beginning when Dr Van Heyningen first found polyols in sugar cataracts in 1959. The involvement of the polyol theory of sugar cataract is described. The prevention of sugar cataract formation by aldose reductase inhibitors dramatically demonstrates the role of this enzyme in sugar-induced cataracts. The possibility of AR involvement of other diabetic complications was an obvious extension of the polyol theory. The use of AR inhibitors in preventing diabetic changes in nerve and retina in animals strongly suggest that AR may play a role in the development of other diabetic complications.

Aldehyde Reductase↗
PubMed1990

The role of lens epithelium in sugar cataract formation.

Previous evidence has shown clearly that sugar cataract formation results from unusually high intracellular levels of polyol. Documentation of polyol-related histological changes in the cortical fiber cells of the equatorial zone has been extensive. However, little attention has been given to the early changes in the lens epithelial cells, in spite of the fact that the highest level of aldose reductase is found in this layer of the lens. Also, cultured lens epithelial cells exposed to high sugar levels exhibit rapid accumulation of polyol and show ultrastructural alterations. Therefore, a study was designed to evaluate the role of the lens epithelium in sugar cataract formation. Specifically, an attempt was made to localize the earliest fine structural lesions in intact lenses of galactose-fed rats and to test their relation to aldose reductase. Rats were fed either a normal diet or a 50% galactose diet with or without sorbinil, an aldose reductase inhibitor. Rats were killed at varying periods of time ranging from 6 to 96 hr, and the eyes were processed for light and electron microscopy. The first detectable abnormalities occurred after 36 hr of galactose feeding, and were limited to the central lens epithelium. Cell edema, apparent dilution of cytoplasm, rounding of nuclei, aberrant intracellular vacuoles, and loss of normal tortuosity of cell boundaries were the salient lesions. No changes were detectable in the equatorial zone until 48 hr, and no deviation from the control structure was found in any of the rats treated with an aldose reductase inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Diabetes-related histopathologies of the rat retina prevented with an aldose reductase inhibitor.

Recent evidence obtained from both galactosemic dogs and rats indicated that aldose reductase inhibitors could prevent several capillary lesions which were similar to those typical of diabetic retinopathy in humans. The present study demonstrates that diabetes-like histopathological changes in the intact retina, which were not visible in the vessel whole mounts used previously, can also be prevented. Sprague-Dawley rats were fed diets containing 50% galactose with or without an aldose reductase inhibitor (tolrestat). After 28 months of galactose feeding, the findings from retinal transections examined by light and electron microscopy were consistent with reports on vessel whole mounts, but showed several additional changes. There was a marked increase in the thickness of the retinal inner limiting membrane, as well as in the capillary basement membranes. There was extensive gliosis and disruption of retinal layers as well as pericyte degeneration, endothelial cell proliferation, accellularity, capillary dilation, and microaneurysm formation. The contents of pericyte compartments in the capillary wall were often replaced with non-pericyte cytoplasm, which appeared glial cell-like. Many of the lumens of acellular capillaries were occluded with debris from degenerating endothelial cells or with cytoplasm possibly originating from glial cell processes. Structures suggestive of degenerated microaneurysms were present mainly in the inner nuclear and outer plexiform layers. The microaneurysms and other major changes were limited to the central and paracentral retina. All these retinal lesions were prevented with orally administered tolrestat. Thus, long-term galactosemia in rats induced histopathologically visible angiopathies, simulating those occurring in background diabetic retinopathy in humans, and these were prevented by treatment with an aldose reductase inhibitor.

Aldehyde Reductase↗
PubMed1990

The effects of sorbinil, an aldose reductase inhibitor, on the corneal endothelium in galactosemic dogs.

Wide-field specular microscopy was used to examine the central corneal endothelium of age- and sex-matched beagle dogs fed for up to 32 months either normal control diets containing 30% nonnutrient filler (13 dogs) or diets containing 30% galactose with (13 dogs) or without (12 dogs) concomitant treatment with the aldose reductase inhibitor, sorbinil. Computerized morphometric analysis of the endothelial cells indicated that a significant decrease in cell density and increase in mean cell area occurred in untreated galactose-fed dogs after 32 months of feeding compared with the normal controls. However, no significant difference could be observed in similar galactose-fed dogs treated with sorbinil. No significant difference in the coefficient of variation of the area, or percent hexagonality of the endothelial cells, or the corneal thickness could be observed in any group. These findings demonstrated that endothelial abnormalities were present in the cornea of the galactose-fed dogs which were similar to those reported for diabetic dogs, rats, and patients and that these changes can be prevented by the concomitant administration of an aldose reductase inhibitor. These findings suggest a role for aldose reductase in the abnormalities noted in the corneal endothelium in diabetes and galactosemia.

Aldehyde Reductase↗
PubMed1989

Localization of aldose and aldehyde reductase in the kidney.

The distribution of NADPH-dependent reductase activity in the rat cortex, outer medulla and inner medulla was investigated through biochemical and histochemical methods. Biochemical studies revealed reductase activity to be present in all three regions of the kidney with the highest specific activity observed in the inner medulla, followed by the cortex and the outer medulla. Activity in all three regions was inhibited by the aldose reductase inhibitors sorbinil, tolrestat and 7-hydroxychromone-2-carboxylic acid. Based on substrate utilization and response to sulfate on the inhibitors, the inner medulla contains primarily aldose reductase (EC 1.1.1.21) while the cortex contains primarily aldehyde reductase (EC 1.1.1.2). The outer medulla contains a mixture of both enzymes. This distribution was confirmed by a radioimmunoassay for aldose reductase. Immunohistochemical investigations of the rat kidney with antibodies against rat lens aldose reductase and rat kidney aldehyde reductase revealed a similar distribution of these enzymes. Aldehyde reductase was immunohistochemically detected only in the cortex where it was localized in the proximal convoluted tubules. Immunoreactive aldose reductase was detected in Henle's loop at both the inner stripe of the outer medulla and in the inner medulla, and in the collecting tubules and the epithelial cell lining the pelvis of the inner medulla near the papilla. No specific immunohistochemical staining for aldose reductase was observed in the cortex. A similar immunohistochemical distribution of aldose reductase was also observed in the human kidney with antibodies against human placental aldose reductase.

Alcohol Dehydrogenase↗
PubMed1989

Diabetic-like retinopathy in rats prevented with an aldose reductase inhibitor.

The earliest histopathologic signs of diabetic retinopathy include selective loss of intramural pericytes and thickening of capillary basement membranes. Previous evidence from animal models indicated that aldose reductase inhibitors could prevent these capillary wall lesions, but only recently have aldose reductase inhibitors been tested for prevention of the subsequent retinal complications of diabetes, such as microaneurysms. In the present study, Sprague-Dawley rats were fed diets containing 50% galactose with or without an aldose reductase inhibitor (tolrestat). After 28 months of galactose feeding, the retinal capillaries in whole mounts exhibited a marked increase in periodic acid-Schiff (PAS) staining, extensive pericyte loss, endothelial cell proliferation, acellularity, diffuse dilation, occluded lumens, microaneurysms, and complex microvascular abnormalities including gross dilation and formation of multiple shunt networks. The PAS hyperchromaticity of basement membrane material and pericyte loss occurred throughout the retinal vasculature, while while the microaneurysms and complex lesions were limited to the capillaries of the central and paracentral retina. The changes were associated with both the arterial and venous portions of the capillary plexus. Treatment with orally administered tolrestat prevented essentially all of the vessel abnormalities. Thus, long-term galactose feeding of rats induced microvascular lesions simulating those occurring in background diabetic retinopathy in humans, and these lesions were prevented by treatment with an aldose reductase inhibitor.

Aldehyde Reductase↗
PubMed1989

Aldose reductase and pericyte-endothelial cell contacts in retina and optic nerve.

Normally, direct contacts between pericytes and endothelial cells occur frequently in both retinal and optic nerve capillaries. The contacts are made through fenestrae in the thick basement membranes which separate the plasma membranes of the two cell types over most of their juxtaposed surfaces. This study was initiated to determine if there was any change in the number of pericyte-endothelial cell contact regions in retinal or optic nerve capillaries of the galactose-fed rat model for polyol-related complications of diabetes. Sprague-Dawley rats were fed for 28 months a 50% galactose diet, with or without an aldose reductase inhibitor (tolrestat), or a normal diet. Electron micrographs of transected capillaries were taken from defined regions of the central retina and nearby portions of the optic nerve. The optic nerve capillaries showed no differences in the numbers of pericyte-endothelial cell contact regions nor in basement membrane thickness in the galactose-fed rats. In contrast, the retinal capillaries exhibited a 70% decrease in the numbers of contact regions and a 2.4-fold increase in basement membrane thickness in galactosemic rats. Both loss of cell contact regions and basement membrane thickening were prevented with tolrestat. The results are consistent with the proposed involvement of the polyol pathway in diabetic retinopathy and with the greater involvement of retinal versus optic nerve vessels in diabetic microangiopathy.

Aldehyde Reductase↗
PubMed1989

[Ciliary body changes associate with aldose reductase in galactosemic rats].

Morphological changes of the ciliary body epithelium in rats fed a 50% galactose diet for 10 months with or without aldose reductase inhibitor (ARI) were investigated by both light microscopic observation and measurement of cell size. Aldose reductase was immunohistochemically observed to be present in non-pigmented epithelial cells of ciliary body and structural change (hypertrophy) was observed only in non-pigmented epithelial cells of galactosemic rats. In contrast, no hypertrophic changes were seen in rats fed with ARI. These results strongly suggest that aldose reductase is associated with hypertrophic change of non-pigmented epithelial cells of the ciliary body.

Aldehyde Reductase↗
PubMed1988

Alteration of a developmentally regulated, heat-stable polypeptide in the lens of the Philly mouse. Implications for cataract formation.

The beta-crystallin basic principal polypeptide (beta Bp) appears to be altered in the lens of the Philly mouse and may be the main defect in this hereditary cataract. Northern blot analysis showed that an mRNA encoding for beta Bp is present in the Philly mouse lens, but normal beta Bp could not be detected. Instead, a different protein related to beta Bp has been observed. Western blot analysis with antibodies against specific beta Bp peptide sequences showed that the Philly protein shares the same amino-terminal residue as beta Bp but lacks a part of the carboxyl-terminal half of normal beta Bp. The altered protein is slightly smaller than beta Bp and has a more acidic isoelectric point by two-dimensional gel electrophoresis. It also lacks the property of heat stability characteristic of normal beta Bp. The mapping of the alteration in beta Bp may give insight into the nature of the heat stability of this protein as well as some indication of the structural components that are necessary to maintain optical clarity in the lens.

Animals↗
PubMed1988

Prevention of pericyte ghost formation in retinal capillaries of galactose-fed dogs by aldose reductase inhibitors.

A distinguishing feature of early diabetic retinal vascular changes is the selective degeneration of pericytes (mural cells) from the retinal capillary vessels. Loss of these pericytes has been proposed to be associated with decreased capillary tonicity, the formation of microaneurysms, and vessel dilation. The role of aldose reductase in the progression of diabetic retinopathy has been investigated in age- and sex-matched beagles fed a 30% galactose diet with or without the aldose reductase inhibitors sorbinil or M79175. Eyes were periodically enucleated from dogs in each group and their retinal capillaries were examined as trypsin-digested flat preparations. Before the clinical appearance of retinal changes, pericyte ghost formation was observed in the eyes of three fourths of the dogs after 21 months and all of the dogs after 24 months of galactose feeding. Many of the capillaries containing pericyte ghosts demonstrated an apparent proliferation of endothelial cells and acellular vessels. No pericyte ghosts or abnormal findings were observed in retinas from either normal control (zero of nine) or galactose-fed dogs treated with aldose reductase inhibitors (zero of 16). These findings indicate that aldose reductase inhibitors can prevent the formation of pericyte ghosts and other subsequent capillary changes in experimental retinopathy.

Animals↗
PubMed1988

Aldose reductase and retinal capillary basement membrane thickening.

Weanling male Sprague-Dawley rats were given a 50% galactose diet with or without an aldose reductase inhibitor (0.04% tolrestat, Ayerst) for 88 weeks. Quantitative computer planimetry on electron micrographs of perpendicularly transected retinal capillaries showed mean basement membrane thicknesses to be 263 +/- 50 nm in galactose-fed rats, 153 +/- 10 nm in galactose-fed rats given tolrestat, and 114 +/- 16 nm in rats given control feed. The retinal capillary basement membrane thickening in galactose-fed rats was accompanied by other ultrastructural alterations mimicking changes observed in diabetic microangiopathy, such as multi-lamination and the formation of vacuoles and dense inclusions. The results extended previously reported (44-week) findings, showed greater galactose-induced changes in capillary basement membranes, and demonstrated the preventative effect of an aldose reductase inhibitor.

Aldehyde Reductase↗