Apoptotic cell death in the lens epithelium of rat sugar cataract

Takamura, Yoshihiro; Kubo, Eri; Tsuzuki, Shosai; Akagi, Yoshio

doi:10.1016/s0014-4835(03)00083-6

Cited by 59 publications

(46 citation statements)

References 23 publications

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“…Based on these observations, we postulated a mechanism for cataract development in SCRs whereby SCR lens epithelial cells unable to synthesize sufficient cholesterol for proper proliferation caused the loss of homeostatic epithelial cell control of the underlying fiber cells, leading to the sequence of biochemical abnormalities observed in the SCR, from increased cellular calcium (9) to calpain activation (10,11), enhancement of proteolysis of crystallins and cytoskeletal proteins (12), and eventually protein insolubilization that is responsible for lens opacification. Intriguingly, it has been pointed out that lens epithelial cell apoptosis could be a common initial cause of noncongenital cataracts (5)(6)(7)(8). A typical lens undergoes a series of changes during the cataractous process.…”

Section: Discussionmentioning

confidence: 99%

“…Lens epithelial cells are essential for maintaining the metabolic homeostasis and transparency of the entire lens, such that it is thought that the continuous occurrence of poorly differentiated epithelial cells at the bow area is responsible for cataract formation in the SCR lens (3). Intriguingly, the lens epithelium is also the initiation site for other types of cataracts, such as selenite-induced cataracts in rabbits (5), UV cataracts in cultured rat lenses (6), rat sugar cataracts (7), and, more importantly, noncongenital cataracts in humans (8).…”

Section: Introductionmentioning

confidence: 99%

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Lanosterol synthase mutations cause cholesterol deficiency-associated cataracts in the Shumiya cataract rat

Mori

Li²,

Abe³

et al. 2006

Journal of Clinical Investigation

103

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The Shumiya cataract rat (SCR) is a hereditary cataractous strain. It is thought that the continuous occurrence of poorly differentiated epithelial cells at the bow area of the lens forms the pathophysiological basis for cataract formation in SCRs. In this study, we attempted to identify the genes associated with cataract formation in SCRs by positional cloning. Genetic linkage analysis revealed the presence of a major cataract locus on chromosome 20 as well as a locus on chromosome 15 that partially suppressed cataract onset. Hypomorphic mutations were identified in genes for lanosterol synthase (Lss) on chromosome 20 and farnesyl diphosphate farnesyl transferase 1 (Fdft1) on chromosome 15, both of which function in the cholesterol biosynthesis pathway. A null mutation for Lss was also identified. Cataract onset was associated with the specific combination of Lss and Fdft1 mutant alleles that decreased cholesterol levels in cataractous lenses to about 57% of normal. Thus, cholesterol insufficiency may underlie the deficient proliferation of lens epithelial cells in SCRs, which results in the loss of homeostatic epithelial cell control of the underlying fiber cells and eventually leads to cataractogenesis. These findings may have some relevance to other types of cataracts, inborn defects of cholesterol synthesis, and the effects of cholesterol-lowering medication.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lanosterol synthase mutations cause cholesterol deficiency-associated cataracts in the Shumiya cataract rat

Mori

Li²,

Abe³

et al. 2006

Journal of Clinical Investigation

103

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“…Subsequently, several laboratories have reported that lens epithelial cell apoptosis is indeed actively involved in lens pathogenesis as demonstrated from in vivo animal model studies. [7][8][9][10][11][12] In addition, both overexpression of various exogenous genes and disruption of certain endogenous genes also lead to lens cell apoptosis followed by abnormal lens formation during lens development. [13][14][15][16][17][18] Apoptosis is regulated by a series of positive and negative regulators.…”

Section: Introductionmentioning

confidence: 99%

Human αA- and αB-crystallins bind to Bax and Bcl-XS to sequester their translocation during staurosporine-induced apoptosis

et al. 2004

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aA-and aB-crystallins are distinct antiapoptotic regulators. Regarding the antiapoptotic mechanisms, we have recently demonstrated that aB-crystallin interacts with the procaspase-3 and partially processed procaspase-3 to repress caspase-3 activation. Here, we demonstrate that human aA-and aBcrystallins prevent staurosporine-induced apoptosis through interactions with members of the Bcl-2 family. Using GST pulldown assays and coimmunoprecipitations, we demonstrated that a-crystallins bind to Bax and Bcl-X S both in vitro and in vivo. Human aA-and aB-crystallins display similar affinity to both proapoptotic regulators, and so are true with their antiapoptotic ability tested in human lens epithelial cells, human retina pigment epithelial cells (ARPE-19) and rat embryonic myocardium cells (H9c2) under treatment of staurosporine, etoposide or sorbitol. Two prominent mutants, R116C in aA-crystallin and R120G, in aB-crystallin display much weaker affinity to Bax and Bcl-X S . Through the interaction, a-crystallins prevent the translocation of Bax and Bcl-X S from cytosol into mitochondria during staurosporine-induced apoptosis. As a result, a-crystallins preserve the integrity of mitochondria, restrict release of cytochrome c, repress activation of caspase-3 and block degradation of PARP. Thus, our results demonstrate a novel antiapoptotic mechanism for a-crystallins. Keywords: aA-crystallin; R116C; aB-crystallin; R120G; Bax; Bcl-X S Abbreviations: a-crystallin, alpha-crystallin; GFP, green fluorescence protein; HaA, human aA-crystallin; HaB, human aB-crystallin; GFP-HaA, green fluorescence and human aAcrystallin fusion protein; GFP-HaB, green fluorescence and human aB-crystallin fusion protein; MEM, Eagle's minimal essential medium; PAGE, polyacrylamide gel electrophoresis; PBS, phosphate-buffered saline; PMSF, phenylmethylsufonyl fluoride; HLE, human lens epithelial cells; SDS, sodium dodecylsulfate; TBS, tris-buffered saline; TBS-T, tris-buffered saline with tween-20.

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“…An intact epithelial cell layer is essential for maintaining water and nutrient flux into and out of the lens body and for the sustained growth of the lens through continuous differentiation of epithelial cells into fiber cells (35). Loss of lens epithelial cells through apoptosis appears to be a common feature of various experimental cataracts (34,51). The role of apoptosis in the development of human senile cataracts is controversial (51,52).…”

Section: Discussionmentioning

confidence: 99%

“…Plasma membrane is essentially the only organelle in these cells. Because all cells derive from the epithelial cells and damage of the epithelium is believed to result in various cataracts, such as those related to diabetes and radiation (34), cultured lens epithelial cells constitute a principal model for studying the mechanisms of cataractogenesis (35). The ease with which bovine cells can be established in primary culture make these cells an especially popular model.…”

Section: Effect Of U18666a On Cultured Blecsmentioning

confidence: 99%

Direct perturbation of lens membrane structure may contribute to cataracts caused by U18666A, an oxidosqualene cyclase inhibitor

Cenedella

Jacob²,

Borchman

et al. 2004

Journal of Lipid Research

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Induction of cataracts in experimental animals is a common toxic feature of oxidosqualene cyclase (OSC) inhibitors. U18666A has been shown to produce irreversible lens damage within a few weeks of treatment. Drug actions, besides reducing the availability of cholesterol, could contribute to cataract formation. Cholesterol added to cultures of lens epithelial cells could only partially overcome the growth-inhibiting effects of U18666A. In view of this finding and the fact that U18666A and other OSC inhibitors are highly lipophilic cationic tertiary amines, we tested the hypothesis that the cataractogenic effect of U18666A is related to direct perturbation of lens membrane structure and function. Based on changes in the anisotropy of fluorescent probes, U18666A incorporated into bovine lens lipid model membranes increased membrane structural order and, using small-angle x-ray diffraction, U18666A was shown to intercalate into the lens lipid model membranes and produce a broad condensing effect on membrane structure. Also, exposure of cultured lens epithelial cells and intact rat lenses to U18666A induced apoptosis. Induction of apoptosis may begin by intercalation of U18666A into cell membranes. By increasing membrane structural order, U18666A may also increase light scatter, thus directly contributing to lens opacification. -Cenedella, R.

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Apoptotic cell death in the lens epithelium of rat sugar cataract

Cited by 59 publications

References 23 publications

Lanosterol synthase mutations cause cholesterol deficiency-associated cataracts in the Shumiya cataract rat

Lanosterol synthase mutations cause cholesterol deficiency-associated cataracts in the Shumiya cataract rat

Human αA- and αB-crystallins bind to Bax and Bcl-XS to sequester their translocation during staurosporine-induced apoptosis

Direct perturbation of lens membrane structure may contribute to cataracts caused by U18666A, an oxidosqualene cyclase inhibitor

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