Oxidative stress, epigenetic regulation and pathological processes of lens epithelial cells underlying diabetic cataract

Abstract

Background

Cataract is a blinding disease worldwide. It is an age-related disease that mainly occurs in people over 65 years old. Cataract is also prevalent in patients with diabetes mellites (DM). The pathological mechanisms underlying diabetic cataract (DC) are more complex than that of age-related cataract. Studies have identified that polyol pathway, advanced glycation end products (AGEs) and oxidative stress are the primary pathogenesis of DC. In recent years, molecular-level regulations and pathological processes of lens epithelial cells (LECs) have been confirmed to play roles in the initiation and progression of DC. A comprehensive understanding and elucidation of how chronic hyperglycemia drives molecular-level regulations and cytopathological processes in the lens will shed lights on the prevention, delay and treatment of DC.

Main text

Excessive glucose in the lens enhances polyol pathway and AGEs formation. Polyol pathway causes imbalance in the ratio of NADPH/NADP⁺ and NADH/NAD⁺. Decrease in NADPH/NADP⁺ ratio compromises antioxidant enzymes, while increase in NADH/NAD⁺ ratio promotes reactive oxygen species (ROS) overproduction in mitochondria, resulting in oxidative stress. Oxidative stress in the lens causes oxidation of DNA, proteins and lipids, leading to abnormalities in their structure and functions. Glycation of proteins by AGEs decreases solubility of proteins. High glucose triggered epigenetic regulations directly or indirectly affect expressions of genes and proteins in LECs. Changes in autophagic activity, increases in fibrosis and apoptosis of LECs destroy the morphological structure and physiological functions of the lens epithelium, disrupting lens homeostasis.

Conclusions

In both diabetic animal models and diabetics, oxidative stress plays crucial roles in the formation of cataract. Epigenetic regulations, include lncRNA, circRNA, microRNA, methylation of RNA and DNA, histone acetylation and pathological processes, include autophagy, fibrosis and apoptosis of LECs also involved in DC.

1. Introduction

Cataract is the leading cause of blindness, accounting for about 51 ​% of all blind people worldwide.¹ It is mainly prevalent in people over 65 years old and patients with diabetes mellitus (DM).² Both Type-1 and Type-2 diabetics are susceptible to develop cataract at an earlier age.³ Epidemiological investigations have shown that as the rise of diabetics, so does the patients with diabetic cataract (DC).⁴ Implantation of an intraocular lens (IOL) instead of cloudy lens by surgery is the only effective way to treat cataract, however, postoperative complications remain unavoidable problems. Some researches indicate that diabetics are at a higher risk of postoperative complications. Herein, understanding the pathogenesis of DC is essential to prevent, delay and treat cataract in diabetics. The purpose of this review is to discuss molecular-level regulations and cytopathological activities of lens epithelial cells (LECs) triggered by high glucose, and how they drive and facilitate the development of cataract.

The lens is an avascular and transparent tissue that is composed of LECs, lens fiber cells differentiated from LECs at the equatorial region and mature fiber cells. Although the metabolic activity is different between LECs and lens fiber cells, glucose metabolism occurs in both LECs and lens fiber cells. Studies have shown that excess glucose in LECs and lens fiber cells results in different outcomes. Chronic hyperglycemia compromises antioxidant capacity and initiates apoptosis in the LECs,^5,6 while causes swelling and liquefaction of lens fiber cells as a result of sorbitol accumulation and osmotic stress.⁷ A large number of studies have demonstrated that polyol pathway, advanced glycation end products (AGEs) and oxidative stress are the primary pathological mechanisms underlying DC.⁸ Polyol pathway and AGEs compromise antioxidant defense system, leading to reactive oxygen species (ROS) accumulation and oxidative stress.⁹ In some cells (e.g., endothelial cells), ROS also enhances polyol pathway and AGEs formation under hyperglycemic condition.¹⁰ In LECs of diabetics^11,12 and diabetic animal models,¹³ oxidative stress plays important roles in the development of cataract according to literatures summarized in Table 1 and Table 2.

Table 1.

Oxidative stress and involvement of oxidative stress underlying diabetic cataract in human.

Materials	Alteration of redox homeostasis	Involvement of oxidative stress	References
Treatment of SRA01/04 with high glucose (50 ​mM, 24 ​h)	Decrease in GSH/GSSG ratio, Total-SOD, CAT, GPx	Lipids peroxidation	81
Human LECs line cultured with high glucose (25.6 ​mM, 7 ​d)	ROS production	Increases in intracellular Ca2+ and apoptosis mediated by TRPV2 upregulation	78
Human LECs cultured with high glucose (125 ​mM, 24 ​h)	ROS production	Activation of unfolded protein response (UPR)	82
LECs from lenses of diabetic cataract	Increases in AKR1B1 expression and SOD2 acetylation	Protein oxidation with an increase in 3-nitrotyrosine level	83,5
Lenses of diabetic cataract	Decrease in GSH, GR, GPx	Protein oxidation	11,84
Plasma and serum of patients with diabetic cataract	Increases in ALR2 and AGEs; decreases in GSH and GPX-3	Lipids peroxidation	42,85
Lenses of diabetic cataract	Increases in RAGE and RAC1(regulatory subunit of NADPH oxidase)	/	86

MDA: malondialdehyde; GR: Glutathione reductase; GPx: Glutathione peroxidase; EMT: epithelial-to-mesenchymal transition; ALR2: aldose reductase 2; AKR1B1: aldo-keto reductases1B1.

Table 2.

Oxidative stress and involvement of oxidative stress underlying diabetic cataract in animal models.

Materials	Alteration of redox homeostasis	Involvement of oxidative stress	References
Lens epithelium of diabetic rats induced by fructose	Increases in ROS and SOD2 acetylation	Protein oxidation with increase in 3-nitrotyrosine (3-NT) level	83
LECs of diabetic rats induced by fructose	ROS production (p47-phox, p67-phox subunits of NOXs and NOX4 upregulation)	/	86,87
LECs of diabetic rats induced by high glucose	AR overexpression (decrease in NADPH/NADP+)	LECs apoptosis	88
LECs of diabetic rats induced by high glucose	ROS generation	Increases in intracellular Ca2+ and apoptosis mediated byTRPV2 upregulation	78
Rat lenses cultured with high glucose, Lens of diabetic rats induced by STZ	Decreases in GSH, Total-SOD, GSH-Px, CAT, α-Klotho and Nrf2	Lipids peroxidation	81,43,13
Lenses of diabetic rats fed with galactose	GSH decrease	UPR activation and LECs apoptosis	82
Lenses of diabetic cataract of STZ induced rats	/	Protein oxidation	32,89
Cataractous lenses of SDH deficient mice	GSH decrease	Lipids oxidation, Na+/K+-ATPase activity reduction, osmoregulatory machinery impairment	90
Lenses of diabetic rats induced by STZ	GSH decrease	Protein and lipids oxidation	91

LECs: lens epithelial cells; STZ: streptozotocin; RAGE: receptor for AGEs; SGLT2: sodium-glucose cotransporter 2; SDH: dehydrogenase; UPR: unfolded protein response; MDA: malondialdehyde.

In addition to the three pathways mentioned above, lncRNA, circRNA, mircoRNA, RNA and DNA methylation, histone acetylation affected by high glucose are regulatory mechanisms mediating survival and apoptosis of LECs. Pathological processes of LECs, include autophagy, fibrosis and apoptosis are also involved in the initiation and progression of DC. This review comprehensively discusses the mechanisms underlying DC and aims to provide theoretical supports for prevention, delay and treatment of DC.

2. Glucose metabolisms and oxidative stress

2.1. Polyol pathway and oxidative stress

Under physiological conditions, glucose is mainly metabolized by glycolysis and citric acid cycle to provide ATP for survival and growth of the lens. About 10 ​% of glucose is metabolized through pentose phosphate pathway to provide sugar residues for nucleotide synthesis, and some of glucose is utilized to synthesize glycogen.¹⁴ Only less than 5 ​% of glucose shunts into polyol pathway due to the low affinity of aldose reductase (AR) to glucose.¹⁵ Under the condition of hyperglycemia, increased glucose levels in aqueous humor prompt excess glucose to be transported into the lens by glucose transporters (e.g., GLUT1, GLUT3 and GLUT5) and sodium-glucose cotransporter (SGLT) on the cell membrane through an insulin-independent manner.¹⁴ Elevation of glucose levels in LECs leads to saturation of hexokinase and restriction of glycolytic pathway. However, both the activity and expression of AR are increased under such condition, approximately 33 ​% of glucose in lens cells shunts into polyol pathway.¹⁶ Glucose is oxidated to sorbitol by AR and sorbitol is reduced to fructose by sorbitol dehydrogenase (SDH), which leads to an reduction in NADPH/NADP⁺ ratio and an increase in NADH/NAD⁺ ratio, respectively (Fig. 1). NADPH is a coenzyme of several antioxidant enzymes, such as glutathione reductase (GR), glutathione peroxidase (GPx) and catalase (CAT). Decrease in NADPH/NADP⁺ ratio impairs the antioxidant capacity of cells, leading to ROS accumulation.¹⁷ Increase in NADH/NAD⁺ ​ratio promotes ROS overproduction in mitochondria.¹⁵

Fig. 1.

Schematic diagram of polyol pathway and oxidative stress. Reduction of glucose to sorbitol by AR leads to decrease in NADPH/NADP⁺ ratio, this compromises generation of GSH from GSSG and the ability of CAT to reduce H₂O₂ to H₂O. Oxidation of sorbitol to fructose by SDH results in increase in NADH/NAD⁺ ratio, NADH is a donor of electron and a higher ratio of NADH/NAD⁺ in the mitochondrial matrix promotes ROS generation.

In vitro, ROS also facilitates polyol pathway by impacting AR under certain conditions.¹⁸ It has been found that superoxide anion radical ($O_2^{·-}$) is the first ROS produced in mitochondria in bovine aortic endothelial cells cultured with high glucose. Normalizing mitochondrial $O_2^{·-}$ prevents high glucose induced ROS generation, indicating $O_2^{·-}$ is a key contributor to ROS induced by high glucose.¹⁹ Enhancement of polyol pathway by ROS may be attributed to the increases in activity and transcription of AR. It has been identified that $O_2^{·-}$ has the ability to quench nitric oxide (NO), which inhibits AR activity by S-thiolation of cystine 298 ​at the active site.²⁰ Although we discuss the impact of ROS on AR according to findings in endothelial cells, this mechanism may be dependent on the cellular context.

2.2. Advanced glycation end products (AGEs) and oxidative stress

Accumulation of AGEs is one of the major risk factors for diabetic complications (e.g., diabetic nephropathy, diabetic retinopathy, diabetic cataract) due to the ability of AGEs to induce oxidative stress and initiate inflammation by binding to their receptor RAGE.²¹ In vitro studies have shown that ROS also enhances AGEs formation in certain conditions.²²

AGEs are a class of heterogeneous compounds that primarily generated by the reactions between carbonyl groups of reducing sugar (e.g., glucose, fructose, galactose) and amino groups of proteins, lipids and nucleic acids, known as Maillard reaction. The processes of AGEs formation are spontaneous that do not require catalysis of enzyme. Under the condition of high glucose, AGEs formation is enhanced due to increases in glucose availability and dicarbonly compounds (e.g., methylglyoxal, 3-deoxyglucosone, glyoxal). Intermediates or byproducts from glycolysis, polyol pathway and lipids peroxidation are also contributor to AGEs (Fig. 2).²³ Studies have shown that AGEs levels in the cataractous lens of diabetics are higher than that without diabetes.³ AGEs induce oxidative stress not only by activating NADPH oxidases (NOXs) through AGEs/RAGE signaling,^24,25 but also reducing activity of antioxidant enzymes by glycation (e.g., site specific or random fragmentation of Cu/ZnSOD).²⁶ In vitro, ROS also enhances AGEs formation through different mechanisms in several types of cells (e.g., retinal vascular endothelial cells).¹⁸ Firstly, $O_2^{·-}$ inactivates glyceraldehyde-3-phosphate dehydrogenase (GAPDH) by oxidation of cysteine residue (Cys-149) at the active site.²⁷ Secondly, ROS caused DNA strand breakage activates poly (ADP-ribose) polymerase-1 (PARP-1), which inactivates GAPDH by mediating GAPDH poly (ADP-ribosyl)ation.²⁸ Thirdly, high glucose also inhibits GAPDH transcription.²⁹ GAPDH is the enzyme that catalyzes the conversion of glyceraldehyde-3-phosphate (GAP) to 1, 3-biphospgoglycerate in the processes of glycolysis. Reduction in GAPDH causes accumulation of GAP, which can be converted into methylglyoxal (MGO), a major precursor of AGEs.³⁰ ROS also enhances AGEs formation by promoting binding of carbonyl groups to amino groups.³¹ Although we discuss the interactions between AGEs and ROS, their interplays in the lens still need to be furtherly explored, especially in the context of high glucose.

Fig. 2.

Pathways for AGEs formation under the condition of high glucose. Intermediates from glycolysis and polyol pathway, such as MGO and 3-DG are primary precursors for AGEs. Higher glucose inside cells enhances Maillard reaction.

3. Molecular-level regulations and cellular pathological processes

3.1. Impairment of biomacromolecules

3.1.1. Protein modifications and insolubility

Proteins in the lens account for 33 ​% of the total weight of the lens, and the high content of proteins is essential for maintaining refractive property and transparency of the lens. Oxidation of proteins changes the structure and function and contributes to lens opacity (Fig. 3). In the development of DC in streptozotocin (STZ) induced rats, the amount of protein carbonyl groups in the lens increases in a time-dependent manner,³² indicating the degree of proteins oxidation is positively correlated with the time of high glucose exposure. Oxidation of proteins alters surface charge and native conformation, causing partial unfolding and exposure of hydrophobic groups. The exposed hydrophobic groups interact with other exposed hydrophobic groups and form aberrant protein-protein interactions, leading to aggregation and insolubility.

Fig. 3.

Pathological mechanisms involved in diabetic cataract. A. Polyol pathway, AGEs, oxidative stress. B. Epigenetic regulations: includes lncRNA, CircRNA, microRNA, methylation of DNA and RNA, histone acetylation. C. Cellular pathological processes: includes autophagy, fibrosis, apoptosis of lens epithelial cells.

Glycation of proteins is also a cause of partial unfolding, exposure of sulfhydryl groups and hydrophobic groups, resulting in formation of disulfide bonds and hydrophobic interactions. Both glycated modifications and abnormal interactions cause cross-linking, high-molecular-weight aggregation and insolubility.³³ Proteins in both intracellular and extracellular matrix (ECM) can be modified by glycation. Glycation of proteins in ECM (e.g., collagen) causes abnormal interactions between collagens and other components or receptors on cell membrane, impairing cellular structure.³⁴

α-Crystallin is the protein with molecular chaperone and anti-apoptotic activity. It is essential to protect other proteins from oxidative damage and apoptosis of LECs. High glucose impairs the molecular chaperone and anti-apoptotic activity of α-crystallin via different modifications, including glycation,³⁵ oxidation,³⁶ and phosphorylation. Glycation of α-crystallin damages the integrity of fiber cells.³⁷ It has been shown that glycation of α-crystallin by MGO causes partial unfolding and decrease in the stability, making it easily degrade.³⁸ In cataractous lens of diabetic rats, phosphorylated level of αB-crystallin is increased, which causes an increase in the fraction of insolubility and formation of cataract.³⁹ Studies have indicated that p38 and ERK1/2 phosphorylate αB-crystallin at Ser59 and Ser45, respectively. Both p38 and ERK1/2 kinases are activated by high glucose and may be responsible for proteins phosphorylation in the development of DC. In vitro, low concentrations (5 and 50 ​mM) of sorbitol subtly changes the secondary and tertiary structure of α-crystallin, reducing the chaperone activity.⁴⁰

3.1.2. Lipids peroxidation

Cell membrane is an important barrier to maintain osmotic balance. Lipids are key components of cell membrane. Although the composition and structure of lipids in lens cell membrane confer them resistance to oxidation, lipids peroxidation also occurs in aging and cataractous lens.⁴¹ In cataractous lenses of diabetics and diabetic rats, the content of malondialdehyde (MDA) is obviously elevated and its concentration is positively correlated with the duration and severity of hyperglycemia,^42,43 indicating high glucose induces lipids peroxidation in the lens.

Lipids peroxidation disrupts the phospholipid bilayer structure of cell membrane, leading to impairment of membrane structure and selective permeability. Lipids peroxidation also causes uncoupling of membrane-bound Na⁺/K⁺-ATPase and oxidative inhibition of Ca²⁺-ATPase in lens cells.⁴⁴ Decrease in Ca²⁺-ATPase activity increases intracellular Ca²⁺ concentration and disturbs osmotic balance.⁴⁵ Besides, lipids peroxides (e.g., MDA, HNE) also damage proteins and DNA due to their longer half-life and the ability to diffuse to distant sites.⁴⁶ Thus, elevation of intracellular Ca²⁺ level and secondary damages to DNA and proteins may be responsible for DC as a consequence of lipids peroxidation (Fig. 3).

3.1.3. Oxidative damages to DNA

Oxidation of DNA influences genome stability, transcription, protein misfolding and cellular damages. Oxidation of DNA causes DNA strand breakage and activation of PARP-1. PARP-1 is the best characterized DNA repair enzyme and plays double roles in H₂O₂ treated lens cells. Medium activity of PARP repairs damaged DNA strand, while prolonged activation of PARP-1 promotes cell death in the lens.⁴⁷ Treatment of human LECs with 30 ​mM glucose for 48 ​h significantly increases poly(ADP-ribosyl)ated protein, indicating PARP-1 activation.⁴⁸ PARP-1 activation results in NAD⁺ decrease and polymers of ADP-ribose (PAR) increase, leading to energy imbalance of cells. In STZ-induced diabetic cataract rats, DNA oxidation marker 8-Hydroxydeoexyguanosine (8-OHdG) in serum is significantly increased.⁴⁹ DNA oxidation contributes to DC through direct or indirect roles (e.g., overactivation of PARP-1) (Fig. 3).

3.2. Epigenetic regulations

3.2.1. LncRNA and miRNA

LncRNA are crucial regulatory molecules related to physical development and multiple diseases, including DC. LncRNA NEAT1 is downregulated in the LECs of patients with DC. It regulates microRNA-205-3p/MMP16 axis in the development of DC.⁵⁰ In high glucose treated HLE-B3 cells, lncRNA PVT1 is upregulated. This inhibits proliferation and promotes apoptosis of LECs by regulating miR-214-3p/MMP2 axis.⁵¹ Circular RNAs (circRNAs) is the covalently closed loop long non-coding RNAs and act as inhibitors (‘sponges’) of microRNA or protein.⁵² In the LECs of patients with DC and high glucose cultured HLE-B3 cells, downregulation of circPAG1 caused by high glucose promotes oxidative stress and apoptosis. It has been identified that circPAG1 acts as a ‘sponge’ of miR-630, which targets to EPHA2. Upregulation of circPAG1 protects high glucose induced oxidative damage to LECs by regulating miR-630/EPHA2 axis.⁵³ In cataractous lenses of diabetics, high glucose induced upregulation of circKMT2E promotes DC by downregulating miR-204-5p. miR-204 inhibits LECs EMT by binding to the 3’-UTR of Smad4.⁵⁴ Upregulation of circKMT2E involves in EMT processes of LECs in the context of high glucose.

MicroRNAs (miRNAs) are key regulatory molecules in physical development and pathological processes by target a majority of mRNAs.⁵⁵ In aqueous humor of patients with DC, miR-551b is significantly upregulated. And this reduces the viability and increases apoptosis of LECs by downregulating CRYAA expression.⁵⁶ Downregulation of miR-30a implicates in DC by targeting SNAL1, an important transcription factor regulating EMT processes.⁵⁷ Both in vivo and in vitro studies in human LECs have indicated that miRNA-199a-5p is downregulated by high glucose. And this induces EMT by regulating SP1.⁵⁸

3.2.2. N⁶-methyladenosine (m⁶A)

m⁶A modification involves in various of RNA biological processes, including transport, splicing, stability, degradation and translation. Treatment of human LECs with high glucose increases RNA methyltransferase like 3 (METTL3) and total m⁶A levels. Upregulation of METTL3 represses proliferation and promotes apoptosis by targeting intercellular adhesion molecule-1 (ICAM-1),⁵⁹ indicating METTL3 not only regulates methylation of mRNA, but also affects fate of LECs under the condition of high glucose.

3.2.3. DNA methylation

Methylation and demethylation of CpG islands in the promoter of DNA are regulatory mechanisms of gene expression by influencing the accessibility of the functional factors in transcriptional machinery.⁶⁰ Kelch-like ECH associated protein 1 (Keap1) is a protein negatively regulates Nrf2, a key nuclear transcriptional factor regulating expression of several antioxidant enzymes in the lens. Studies have shown that high glucose regulates methylation levels in the promoter region of Keap1. In the lenses of patients with DC, methylation level in the promoter of Keap1 is significantly decreased, and this increases its expression of mRNA and protein. Increase in Keap1 promotes Nrf2 degradation that downregulates transcription of several antioxidant enzymes. Thus, demethylation of Keap1 implicates in DC by aggravating oxidative stress and proteins aggregation.⁶¹ It has been revealed that increase of MGO may be responsible for keap1 demethylation under the condition of high glucose.⁶²

3.2.4. Histone acetylation

Histone acetylation enhances gene expression by relaxing chromatin. Histone deacetylation suppresses gene expression due to the unmodified histones possess a positive charge. In this situation, histones interact more closely with the negatively charged DNA backbone, leading to condensation of chromatin and restriction of transcriptional machinery.⁶³ In galactose induced rats, the formation of cataract is attributed to upregulation of Polo-like kinase 3 (Plk3) mRNA. Mechanically, overexpression of Polo-like kinase 3 (Plk3) mRNA is regulated by histone acetylation.⁶⁴ This implies that acetylation and deacetylation are one of the regulatory mechanisms underlying galactose induced cataract in rats.

3.3. Cellular pathological processes

3.3.1. Autophagy of LECs

Autophagy is a catabolic process implicated in both cellular survival and death. It degrades defective or aggregated proteins, lipids, toxic debris, as well as disused organelles and membrane. It has been shown that alternations in autophagic activity are associated with cataract.⁶⁵ Exposure of HLE-B3 cells to high glucose results in a decrease in autophagic activity and activation of EMT.⁶⁶ In high glucose treated HLE-B3 cells, inhibition of autophagic activity is correlated with EMT processes. NICD/ULK1 signaling is confirmed to mediate the crosstalk between autophagy and EMT processes in the development of DC.⁶⁷ In high glucose cultured SRA01/04 ​cells and lens epithelium of patients with DC, autophagic activity is significantly suppressed. Downregulations of AMPK-dependent FOXO3 and TFEB are the regulatory mechanisms of autophagy inhibition induced by high glucose.⁶⁸ Both in vivo and in vitro studies in LECs of mice demonstrate inhibition of autophagy induced by high glucose is related to oxidative damage.⁶⁹

3.3.2. Fibrosis of LECs

Fibrosis of LECs destroys the morphological structure and causes abnormal deposition of ECM (e.g., collagen), leading to LECs hardness and loss of elasticity. Both TGFβ1 and TGFβ2 are highly expressed in aqueous humor and lens epithelium of patients with DC. Moreover, the expression of TGFβ is positively correlated with the level of glycosylated haemoglobin.⁷⁰ TGFβ is the most effective inductor of fibrosis, suggesting high glucose may promote LECs fibrosis by stimulating TGFβs expression. In lens epithelium of diabetics, LECs EMT is also associated with the increase in RAGE.⁵ AGEs/RAGE activates or participates in signaling pathways to regulate EMT. It has been found that AGEs/RAGE also involves in TGF-β signaling in the processes of EMT in LECs.⁷¹ In diabetic animal models, fibrosis of LECs is also indueced by AR.⁷²

3.3.3. Apoptosis of LECs

In the lenses of patients with DC, apoptosis of LECs is obviously observed.⁷³ In lens epithelium of diabetics, apoptosis of LECs is evidenced by expression of Bax/Bcl-2,⁷⁴ p53 and caspase-8.⁷⁵ Oxidative stress induced by high glucose is also an initiator of apoptosis in human LECs.76, 77, 78 Elevation of intracellular Ca²⁺ induced by high glucose also mediates apoptosis of LECs. Both in vivo and in vitro experiments suggested that disruption of Ca²⁺ homeostasis enhances apoptosis of human LECs and contributes to lens opacity.⁷³ Exposing ex vivo lenses of rats to galactose aggravates apoptosis of LECs, indicating accumulation of sugar alcohols is also a risk factor for LECs apoptosis and DC.⁷⁹ In STZ induced diabetic rats, apoptosis of LECs at the central of anterior capsule and equatorial zones is remarkably observed. And this is related to the reduction of NGF level.⁸⁰

4. Conclusions

Oxidative stress plays key functions in the formation of cataract in both diabetics and diabetic animal models. Additionally, epigenetic regulations, autophagy, fibrosis and apoptosis of LECs also implicated in the initiation and progression of DC according to findings, which are mainly derived from in vitro studies of human cell lines.

Study approval

The study obtains approval of Shaanxi Eye Hospital, Xi'an People's Hospital (Xi'an Fourth Hospital), Affiliated People's Hospital of Northwest University.

Author contributions

The authors confirm contribution to the paper as follows: Conception and design of study: HY; Drafting the manuscript: ZG; Figures and Tables set up: XM; Revision of Manuscript: RZ. All authors reviewed the results and approved the final version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (Grant Nos. 81873674 and 82070947).

Declaration of competing interest

The authors declare that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Abbreviations

DC

Diabetic cataract

LECs

Lens epithelial cells

AGEs

Advanced glycation end products

RAGE

Receptor for advanced glycation end products

ROS

Reactive oxygen species

$O_2^{·-}$

Superoxide anion radical

NOXs

NADPH oxidases

GSH

Glutathione

GSSG

Glutathione disulfide

H₂O₂

Hydrogen peroxide

CAT

Catalase

SOD

Superoxide dismutase

GPx

Glutathione peroxidases

NAD⁺

Oxidized nicotinamide adenine dinucleotide

NADH

Reduced nicotinamide adenine dinucleotide

NADP⁺

Nicotinamide adenine dinucleotide phosphate

NADPH

Nicotinamide adenine dinucleotide phosphate hydrogen