Downregulation of gene expression in the ageing lens: a possible contributory factor in senile cataract

ABSTRACT _PURPOSE_ To study the molecular characteristics of lens epithelial cells from patients with senile cataract by cDNA microarray technique. _METHODS_ Lens epithelial cells adhering

to anterior capsules taken during cataract surgery collected from 108 patients, aged 56−92 years (senile cataract group), were pooled. Pooled epithelial cells of normal, noncataractous

lenses from one patient with ocular trauma, one patient with lens subluxation, and 25 cadaveric eyes, all under the age of 55 years, served as a control. Total RNA was extracted by

conventional methods from the two groups of cells, and a fluorescent probe was prepared for each group. The probes were hybridized on 9700 known human cDNA clones. Hybridized clones were

analysed using a scanning laser and the results were processed by GEMTools (Incyte Genomics) software. _RESULTS_ A total of 1827 clones hybridized with the two probes. Of these, 400 showed

differences of more than two-fold in gene expression between the two probes. Relative to controls, gene expression in the senile cataract lenses was upregulated in 318 clones and

downregulated in 82. Three genes-filensin, inwardly rectifying potassium channel (IRPC), and pigment epithelium-derived factor (PEDF) were strongly downregulated (by 41.3-, 6.8-, and

5.9-fold, respectively) in senile cataract. _CONCLUSIONS_ Cataractogenesis is associated with numerous changes in the genetic profile of the lens epithelial cells. Since filensin, IRPC, and

PEDF genes are known to have important roles in the physiology and morphology of the transparent lens, substantial downregulation of their expression might contribute to the formation of

senile cataract. SIMILAR CONTENT BEING VIEWED BY OTHERS GENE PROFILES AND MUTATIONS IN THE DEVELOPMENT OF CATARACTS IN THE ICR RAT MODEL OF HEREDITARY CATARACTS Article Open access 24

October 2023 ABSENCE OF S100A4 IN THE MOUSE LENS INDUCES AN ABERRANT RETINA-SPECIFIC DIFFERENTIATION PROGRAM AND CATARACT Article Open access 26 January 2021 ALTERED GENE EXPRESSION IN

_SLC4A11__−/−_ MOUSE CORNEA HIGHLIGHTS SLC4A11 ROLES Article Open access 22 October 2021 INTRODUCTION The adult lens is a transparent, biconvex structure composed of one cell type, the lens

epithelium. Epithelial cells at the anterior surface of the lens produce a basal membrane, the lens capsule, which coats the lens surface. The epithelial cells migrate towards the bow region

of the lens, where they begin to undergo terminal differentiation into lens fibres, a process that includes the loss of all major organelles, massive cell elongation, and the expression of

proteins specific to lens fibre cells. Normal lens metabolism requires an appropriate internal ionic−osmotic milieu, which in turn depends on communication between the epithelial cells and

the lens fibres. Sodium/potassium-dependent ATPase channels are found at their highest concentration in the epithelium in order to maintain this unique milieu.1, 2 The cytoplasm of the lens

fibre cells (LFCs) contains crystallins, a class of water-soluble proteins believed to minimize scattering of the light that passes through it. The LFCs are organized in concentric layers

connected by intercellular junctions.1, 3 These cells possess a well-organized, spectrin–actin membrane cytoskeleton that consists of two different types of intermediate filaments: vimentin,

which is spread throughout the cytoplasm, and ‘beaded-chain filaments’, composed of the lens-specific proteins filensin and phakinin. Filensin, a 115-kD intermediate filament protein, is

believed to be functionally important in LFC differentiation and in maintaining LFC conformation and transparency.4, 5, 6 Cell lines of murine and rabbit lenticular origin were shown to

overexpress the filensin gene.7 Pigment epithelium-derived factor (PEDF), a 50-kDa secreted protein, is a member of the serpin family of proteins, and is expressed in all ocular tissues of

the human eye.8 PEDF accumulates in the aqueous humour.9 It acts as a survival factor, protecting neuronal cells from natural and induced apoptosis.10 Lens function deteriorates with age.

Oxidative stress, ultraviolet radiation, and other toxic factors can induce the formation of cataract _in vitro_ and _in vivo_.1, 11 The formation of senile cataract is a universal ageing

process accompanied by numerous morphological and functional changes in the lens cells. This study was undertaken to investigate the molecular characteristic of lens epithelial cells from

patients with senile cataract. We started out with some basic assumptions. (a) The ageing process is manifested by DNA transcriptional changes, which result in alteration of protein

expression. Thus, senile cataract is characterized by upregulation and downregulation of genes, manifested by over- or underexpression of their corresponding RNA species. These changes are

detectable in senile cataractous lenses. (b) The ageing process eventually leads to cell death by either an active process of apoptosis (programmed cell death) or by senescence. Apoptosis of

lens epithelial cells appears to be a common cellular basis for noncongenital cataract (including senile) development in humans and animals.12 (c) The lens is composed of one type of cell,

the epithelium, and any genetic alterations will be expressed in these cells. (d) The epithelial cells adhere to the anterior capsule of the lens and can be extracted from there. Since the

number of lens epithelial cells from one individual is limited, we had to accumulate numerous samples and assume that they all share the same pathological pattern of senile cataract. Using

microarray-based technology, which makes it possible to screen thousands of genes simultaneously, we analysed gene expression in the human cataractous lens. METHODS PATIENT DATA Lens

epithelial cells adhering to anterior lens capsule taken during routine cataract surgery were collected, and the cells from 108 patients (62 women and 46 men), ranging in age from 56 to 92

years (mean age 74. 6 years) were pooled (senile cataract group). The mean ages of the women and the men were 76.3 years and 72.2, respectively. Exclusion criteria were age below 55 years,

diabetes mellitus, pseudoexfoliation of the eye, traumatic cataract, a history of topical or systemic steroid treatment, and uveitic disease. During the week before cataract surgery patients

underwent slit lamp examination and their cataracts were classified for the type and severity of the opacity by an experienced examiner according to Lens Opacities Classification Scale

(LOC)-II grading system.13 Our senile cataract group consisted of 63% mixed cataract, 25% nuclear cataract, 7% cortical, and 5% posterior subcapsular. Anterior capsule-epithelium samples of

5–5.5 mm diameter were taken during surgery by capsulorhexis and were immediately washed by a balanced salt solution (BSS). Then, the capsules were placed in sterile tubes, immersed in

liquid nitrogen at −180°C, and stored at −80°C. The pooled epithelial cells adhering to the anterior lens capsules of normal, non-cataractous lenses from one patient with blunt ocular trauma

who had undergone surgery for subluxated clear lens, one patient with essential subluxated lens, and 13 cadavers (25 eyes) (aged 2−54 years) served as a control. Clear whole lenses from

organ donors were obtained within 12 h post mortem. The lenses were microscopically examined for opacities and those lenses displaying opacity were excluded from the study. The anterior

capsules for central epithelium (7–8 mm2) were dissected and lens fibres removed to prevent contamination. The anterior capsules were placed in sterile tubes and immersed in liquid nitrogen

at −180°C, and in a later stage were stored in −80°C. RNA EXTRACTION Total RNA was extracted by conventional methods from the epithelial cells adhering to the capsules.14, 15, 16 RNA was

isolated using the Trireagent™ protocol. Briefly, 1 ml of a mixture of guanidine thiocyanate and phenol in a mono-phase solution (Trireagent™) was added to every 10 frozen capsules.

Following denaturation of proteins, bromochloropropane was added and the RNA was separated by centrifugation (14000 _g_ for 10 min at 4°C). The interphase containing DNA and the lower

organic phase containing proteins were discarded, and total RNA was collected from the upper aqueous phase. Isopropanol was added and the mixture was centrifuged at 12000 _g_ for 15 min at

4°C. The RNA pellet was washed with 75% ethanol, vortexed, and repelleted by centrifugation at 7500 _g_ for 5 min at 4°C. The final RNA pellet was air dried and dissolved in water by

repeated pipetting for 10 min at 60°C. RNA concentrations were measured by a spectrophotometer at 260 nm. RNA quality was assessed by running 0.5–1 _μ_g of RNA on 1% agarose gels. Samples

that were found to contain degraded RNA were discarded. Good-quality RNA from the 15 pooled noncataractous lenses yielding 50 _μ_g of total RNA (a sufficient amount for probe synthesis) and

from a pooled sample of senile cataract lenses that yielded 50 _μ_g of total RNA was used for synthesis of cDNA probes.14, 15 PROBE LABELLING AND HYBRIDIZATION TO DNA MICROARRAYS From each

of the 50-_μ_g RNA pools, a cDNA probe was synthesized using reverse transcriptase–polymerase chain reaction (RT–PCR) (Superscript, Gibco-BRL) and an 18-mer oligo-dT primer. For

hybridization of the probes, we used a commercially available human microarray, UniGEM1 (Incyte Genmics, Fremont, CA, USA), containing 9700 human cDNA clones, 60% of them coding for known

genes. During the RT reaction, the cDNA in the hybridization probe derived from the senile cataract sample was labelled with Cy3-dCTP (Amersham) and the cDNA from the normal lenses with

Cy5-dCTP (Amersham).14, 15 Hybridization and subsequent scanning, visualization, and quantization of the results were performed using the GEMTools software (Incyte Genomics, Fremont, CA,

USA). This software generates significant differences between gene expressions where, a two-fold difference is equal to a _P_-value of 0.05.14, 15, 16, 17 All differential expression values

were log transformed and balanced, essentially as previously described.17 Briefly, the differential values were calculated only if the signal to background ratio exceeded 2.0, the signal

intensity was above 200 U in at least one of the two channels, and the element diameter exceeded 40% of the mean element diameter for the array. RESULTS Anterior capsules from 27 clear

lenses and from 108 lenses with senile cataracts were used for total RNA extraction. It should be stressed that RNA from lenses of the same cadaver was extracted separately, and separately

assessed by ethidium bromide microgel, electrophoresed, scanned, and analysed for quality and quantity. In all, 12 of the 27 control cadaveric lenses were found to contain degraded RNA and

were therefore excluded from further analysis. All 12 of these RNA samples had been obtained 4 h or more after death, whereas the rest of the cadaveric lenses used in this study, all of

which contained RNA of good quality, had been obtained 3 h or less after death. Similarly, among the samples obtained from senile cataractous lenses only those containing nondegraded RNA

were used for this study. Thus, although more cataract samples were initially collected, only 108 were included in the analysis. Scanning of the microarray of 9700 clones with each of the

hybridization probes revealed that 1827 clones showed a detectable hybridization signal with either the clear lens or the cataractous lens probe (See Figure 1). Expression of 400 of the

clones in the control and the cataract-derived cDNA probes the differed by a factor of more than two. The differential in the fluorescent signal for a particular gene represents the actual

mRNA level of these genes within each probe. A two-fold down- or upregulation is generally considered a significant result. Three genes, filensin, inwardly rectifying potassium channel, and

PEDF, were found to be substantially downregulated in senile cataract lenses. The differential expression pattern of each of these genes is recorded in Table 1. All three showed high

fluorescent signals in clear lenses, and significantly lower signals in cataractous lenses. DISCUSSION The results of this study showed that the filensin gene was downregulated 41. 3-fold in

lenses with senile cataract. The primary sequence, secondary structure, and unique gene structure of the filensin human gene were described by Hess _et al_ in 1998.18 The intermediate

filament (IF) proteins of the lens form two morphologically distinct polymers: (a) 10 nm thick intermediate filaments and (b) beaded filaments, a highly specialized network of obligate

heteropolymers juxtaposed to the plasma membrane, which is composed of two lens-specific polypeptides, filensin, and phakinin.19, 20 Filensin is a 115-kDa cytoskeletal membranal protein.

Indirect immunofluorescence and immunoelectron microscopy show that filensin appears to be concentrated at the periphery of the hexahedral LFCs.5 The cytoplasm of the LFCs is filled with

crystallins, a class of water-soluble proteins believed to refract the light and minimize its scattering as it passes through the eye.1 Alpha B-crystallin, a small heat-shock protein

expressed at high levels in the lens, selectively targets the intermediate filament proteins filensin and phakinin for protection against unfolding during conditions of stress, thereby

protecting against cataract formation.21 Filensin is believed to be functionally important in the differentiation of LFCs and the maintenance of their conformation and transparency.4, 22, 23

The intermediate filament vimentin does not appear to play a major role in lens function. Knockout of the lens' single vimentin gene in the mouse does not affect lens morphogenesis or

the overall architecture of the LFCs.20 In contrast, reduced synthesis of filensin in a mutant mouse strain has been correlated with severe developmental defects, such as the inability of

the LFCs to elongate.24, 25 The results of a recent analysis of the lens proteins from 10 young patients after cataract operations led to the suggestion that changes in cytoskeletal proteins

may contribute to congenital and childhood cataracts.26 The results of the present study showed significant downregulation of the filensin gene in the senile cataract group. Given the

importance of this lens cytoskeleton component in maintaining the conformation and transparency of the lens, it seems likely that the filensin gene plays a key role in cataract development,

where the structure of the lens is disrupted. In this study, the inwardly rectifying potassium channel gene was downregulated by 6.8-fold in lenses with senile cataract. Potassium

conductance is essential for maintenance of the volume and transparency of the lens. Three major potassium current channels exist in lens cells: (a) an outwardly rectifying current channel,

(b) a calcium-activated current channel, a conductance channel that is activated by calcium at its inner surface and participates in cell signalling, transepithelial transport, and volume

regulation,27 and (c) an inwardly rectifying current channel, comprising a family of more than 10 members.28 These three K+ channels play a pivotal role in determining resting membrane

potential, regulating action potential duration, and transporting K+ ions, and therefore contribute substantially to the functioning of lens epithelial cells.29 The involvement of inwardly

rectifying K+ channel in cataract formation has not been documented. Retinal glial cells obtained from patients suffering from vitreoretinal or chorioretinal diseases show partial or

complete loss of inwardly rectifying potassium currents.30 However, reduction in the expression of inwardly rectifying potassium channel gene in lens epithelial cells affects the morphology

and transparency of the lens, and may therefore be associated with cataract formation. The gene for PEDF was found to be downregulated 5.9-fold in lenses with senile cataract in our study.

The retinal pigment epithelium (RPE) is a highly specialized neuroepithelium, which develops in advance of and lies adjacent to the interphotoreceptor matrix. The RPE, which plays a critical

role in retinal homeostasis, synthesizes and secretes many soluble products into the interphotoreceptor matrix, among them PEDF,8, 9, 10 a 50-kDa member of the serpin (serine protein

inhibitor) family. PEDF is expressed intracellularly in almost all human ocular tissues and extracellularly during both foetal and early adult periods.8, 9, 10, 31 It is also expressed by

cells other than RPE, such as cultured foetal lung fibroblasts, where its downregulation is linked to the process of senescence.32 PEDF has been detected in the eyes of human fetuses at 17

weeks of gestation. Relative to this, PEDF secreted by human foetal RPE cells in culture was shown to induce neuronal differentiation of human retinoblastoma cells _in vitro_.33, 34, 35 It

also acts as a survival factor, protecting neuronal cells from natural and induced apoptosis.33 The loss of PEDF in senescent cells and in differentiated retinoblastoma cells suggests that

this protein might be involved in terminal differentiation and ageing.33 The association of intracellular PEDF with cytoskeletal structures and its colocalization with actin point to the

possibility that it may be a microfilament-binding protein. Thus, PEDF could be involved in maintaining the stability of cytoskeletal structures.8 Taken together, the above findings strongly

suggest that the observed downregulation of PEDF in lenses with senile cataract in the present study is likely to be relevant to cataractogenesis. In summary, this study demonstrates a

significant downregulation of three genes—filensin, inwardly rectifying potassium channel gene, and PEDF gene—in epithelial cells from lenses with senile cataract. Each of these genes has a

key physiological and structural role in the lens. It thus seems that the underexpression of each of these genes can induce cataract formation. Moreover, their combined downregulation

provides a possible mechanism for the disruption of lens morphology, which may lead to cataract. Further study of the effects of these genes, and of as yet uncharacterized genes that play

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Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Ophthalmology, Meir Hospital, Sapir Medical Center, Kfar-Saba, Israel F Segev, A Segev & E I

Assia * Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel F Segev, M Belkin & E I Assia * QBI Laboratories, Ness-Ziona, Israel O Mor * Goldschleger Eye Research

Institute, Sheba Medical Center, Tel Hashomer, Israel M Belkin Authors * F Segev View author publications You can also search for this author inPubMed Google Scholar * O Mor View author

publications You can also search for this author inPubMed Google Scholar * A Segev View author publications You can also search for this author inPubMed Google Scholar * M Belkin View author

publications You can also search for this author inPubMed Google Scholar * E I Assia View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING

AUTHOR Correspondence to F Segev. ADDITIONAL INFORMATION This work had been orally presented in part at the 2001 ARVO Annual meeting. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT

THIS ARTICLE CITE THIS ARTICLE Segev, F., Mor, O., Segev, A. _et al._ Downregulation of gene expression in the ageing lens: a possible contributory factor in senile cataract. _Eye_ 19, 80–85

(2005). https://doi.org/10.1038/sj.eye.6701423 Download citation * Received: 03 July 2003 * Accepted: 28 November 2003 * Published: 23 April 2004 * Issue Date: 01 January 2005 * DOI:

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currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * cataractogenesis * gene expression * filensin *

potassium transport * PEDF