Selective pericyte degeneration in the retinal capillaries of galactose-fed dogs results from apoptosis linked to aldose reductase-catalyzed galactitol accumulation

Murata, Masatoshi; Ohta, Nobuo; Fujisawa, Shigeki; Tsai, Jen-Yue; Sato, Sanai; Akagi, Yoshio; Takahashi, Yukio; Neuenschwander, Heike; Kador, Peter F.

doi:10.1016/s1056-8727(01)00171-4

Cited by 30 publications

(28 citation statements)

References 21 publications

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“…rat, and bovine retinas by a number of laboratories. 10,[13][14][15]34,35 The present studies agree with previous observations that hyperglycemia-associated sorbitol accumulation is linked to retinal capillary pericyte apoptosis and that this apoptosis is reduced by the presence of AR inhibitor (Figs. 7, 8).…”

Section: Discussionsupporting

confidence: 93%

“…Studies using primary cultures from human, dog, and bovine retinal capillaries all indicate that pericytes contain AR and that AR activity is linked to the induction of apoptosis in retinal capillaries exposed to either hyperglycemia or galactosemia. [12][13][14][15] However, reports using rat retinal capillary pericytes and endothelial cells have been minimal despite the fact that rats have been widely used to investigate the development of DR. This may in part be due to the diffi culty of obtaining adequate amounts of retinal vascular tissue from the rat eye compared to the bovine eye, which is the most common source of retinal capillary cells.…”

Section: Sugar Analysis Of Cultured Cellsmentioning

confidence: 99%

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Polyol Formation in Cell Lines of Rat Retinal Capillary Pericytes and Endothelial Cells (TR-rPCT and TR-iBRB)

Kador

Randazzo

Blessing

et al. 2009

Journal of Ocular Pharmacology and Therapeutics

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Section: Discussionsupporting

confidence: 93%

Section: Sugar Analysis Of Cultured Cellsmentioning

confidence: 99%

Polyol Formation in Cell Lines of Rat Retinal Capillary Pericytes and Endothelial Cells (TR-rPCT and TR-iBRB)

Kador

Randazzo

Blessing

et al. 2009

Journal of Ocular Pharmacology and Therapeutics

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“…13,[15][16][17][18] In the development of diabetes and its diabetic complications, cellular responses to hyperglycemia, its fluctuations, and the induction of hypoglycemia have been recently linked to stress of the endoplasmic reticulum (ER). [19][20][21][22][23][24][25][26] In addition to being the primary intracellular compartment responsible for protein biosynthesis and folding, the ER is a signaltransducing site that responds to various cellular stressors that include hypoxia, oxidative stress, osmotic stress, and glucose levels.…”

mentioning

confidence: 99%

“…These communications are central to vessel assembly, growth control, and normal function. 43 The selective loss of pericytes has been reported to be the hallmark of DR 44,45 and pericyte loss in dogs has been linked to AR activity 17,46,47 ; however, the selective loss of pericytes versus endothelial cells is controversial. [48][49][50][51][52] Using rat retinal capillary pericyte (TR-rPCT) and endothelial (TR-iBRB) cells, we have previously reported that short-term hyperglycemia results in pericyte apoptosis that is linked to the AR-catalyzed accumulation of sorbitol and that pericytes exposed to hypoglycemia demonstrate ER stress-linked apoptotic signaling.…”

mentioning

confidence: 99%

Response of Rat Retinal Capillary Pericytes and Endothelial Cells to Glucose

Makita

Hosoya

Zhang

et al. 2011

Journal of Ocular Pharmacology and Therapeutics

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Aim: The purpose of this study was to investigate the effects of hyperglycemia, its fluctuations, and glucose starvation on the expression of glucose-regulated protein 78/binding immunoglobulin protein (GRP78/BiP), one of the most commonly used markers of endoplasmic reticulum stress, in rat capillary pericytes and endothelial cells cultured separately and together. Methods: Conditionally immortalized rat retinal pericyte and endothelial cell lines were cultured in dishes coated with collagen type I in Dulbecco's modified Eagle's medium containing 5.5 mM glucose. For cocultures, pericytes and endothelial cells were seeded together on rat tail collagen type I-coated cell culture plates. After 24 h of initial culture, the medium was replaced with serum-free medium containing 0-100 mM glucose for periods of up to 72 h. GRP78/BiP, caspase-3, and nuclear factor-kB expression were investigated using western blots. Results: No significant increase in GRP78/BiP expression was observed when pericytes, endothelial cells, or cocultures were exposed to either 25, 50, or 100 mM glucose for 48 h compared with the control level of 5.5 mM glucose. Similarly, no change in expression of GRP78/BiP was observed when media glucose levels were reduced from either 5.5 or 25 to 1 mM. GRP78/BiP expression significantly increased when cells were cultured for 24 h in glucose-deprived medium. This was accompanied by a time-dependent increase in the expression of caspase-3 and nuclear factor-kB. Conclusion: In diabetic retinopathy, hyperglycemia has been reported to induce apoptosis in retinal capillary vascular cells, but these studies suggest that the apoptosis is not linked to the expression of GRP78/BiP, one of the most commonly used markers of endoplasmic reticulum stress. However, GRP78/BiP-linked apoptosis may play a role in vascular changes associated with retinal ischemia/reperfusion.

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“…Hyperglycaemia-mediated pericyte dysfunction and, ultimately, premature pericyte death are a major pathogenic consequence of diabetic retinopathy [5], although the precise nature of the biochemical insult and of the subsequent death response remains illdefined. A range of in vitro and in vivo studies have demonstrated that retinal pericytes enter an apoptosisrelated death pathway after long-term diabetes in humans [6,7], during experimental diabetes or hyperhexosaemia [8,9], and after exposure to biochemical insults in culture [10,11].…”

Section: Introductionmentioning

confidence: 99%

Substrates modified by advanced glycation end-products cause dysfunction and death in retinal pericytes by reducing survival signals mediated by platelet-derived growth factor

et al. 2004

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Aims/hypothesis. Premature death of retinal pericytes is a pathophysiological hallmark of diabetic retinopathy. Among the mechanisms proposed for pericyte death is exposure to AGE, which accumulate during diabetes. The current study used an in vitro model, whereby retinal pericytes were exposed to AGE-modified substrate and the mechanisms underlying pericyte death explored. Methods. Pericytes were isolated from bovine retinal capillaries and propagated on AGE-modified basement membrane (BM) extract or non-modified native BM. The extent of AGE modification was analysed. Proliferative responses of retinal pericytes propagated on AGE-modified BM were investigated using a 5-bromo-2-deoxy-uridine-based assay. The effect of extrinsically added platelet-derived growth factor (PDGF) isoforms on these proliferative responses was also analysed alongside mRNA expression of the PDGF receptors. Apoptotic death of retinal pericytes grown on AGE-modified BM was investigated using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling labelling, mitochondrial membrane depolarisation and by morphological assessment. We also measured both the ability of PDGF to reverse Akt dephosphorylation that was mediated by AGE-modified BM, and increased pericyte apoptosis. Results. Retinal pericytes exposed to AGE-modified BM showed reduced proliferative responses in comparison to controls (p<0.05-0.01), although this effect was reversed at low-AGE modifications. PDGF mRNA levels were differentially altered by exposure to low and high AGE levels, and AGE-modified BM caused significantly increased apoptosis in retinal pericytes. Pre-treatment of AGE-modified BM with PDGF-AA and -BB reversed the apoptosis (p<0.05-0.001) and restored Akt phosphorylation in retinal pericytes. Conclusions/interpretation. Evidence suggests that substrate-derived AGE such as those that occur during diabetes could have a major influence on retinal pericyte survival. During diabetic retinopathy, AGE modification of vascular BM may reduce bioavailability of pro-survival factors for retinal pericytes.

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Selective pericyte degeneration in the retinal capillaries of galactose-fed dogs results from apoptosis linked to aldose reductase-catalyzed galactitol accumulation

Cited by 30 publications

References 21 publications

Polyol Formation in Cell Lines of Rat Retinal Capillary Pericytes and Endothelial Cells (TR-rPCT and TR-iBRB)

Polyol Formation in Cell Lines of Rat Retinal Capillary Pericytes and Endothelial Cells (TR-rPCT and TR-iBRB)

Response of Rat Retinal Capillary Pericytes and Endothelial Cells to Glucose

Substrates modified by advanced glycation end-products cause dysfunction and death in retinal pericytes by reducing survival signals mediated by platelet-derived growth factor

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