# Roles of Lens Aquaporins and GPX1 in Hydrogen Peroxide Balance, Homeostasis, and Aging

> **NIH NIH R01** · STATE UNIVERSITY NEW YORK STONY BROOK · 2022 · $398,750

## Abstract

PROJECT SUMMARY/ABSTRACT: Our long-term goal is to contribute to the prevention and treatment of
cataracts, which are the major global cause of visual impairment. Age-related lens optical aberrations manifest
around age forty and gradually progress into a cataract. Accrual of Hydrogen peroxide (H2O2) due to UV
radiation, normal cellular metabolism, etc., is a major cause of age-related cataract (ARC) formation. The
scavenging activity of Glutathione (GSH) and Glutathione Peroxidase 1 (GPX1) helps to detoxify cellular H2O2.
As the lens ages, GPX1 activity is reduced, causing gradual H2O2 accumulation which affects homeostasis and
transparency. Homeostasis of the avascular lens significantly depends on microcirculation to carry in nutrients
and eliminate metabolic waste. Aquaporin (AQP) water channels and Connexin (Cx) gap junction channels are
integral to the lens microcirculation. Lens epithelial cells express AQP1, AQP5, Cx43 and Cx50, and fiber cells
express AQP0, AQP5, Cx46 and Cx50. AQP0, the most abundant lens membrane protein, exists as intact and
end-cleaved forms. Mutation or knockout (KO) of AQP0, Cx46 and Cx50 causes cataracts. Under stressful
conditions, AQP1 or AQP5 KO lenses develop cataracts. Lens Cxs play a role in transporting GSH to the nucleus.
Our preliminary intact lens studies show that lenticular AQPs are permeable to H2O2. In this grant proposal, we,
for the first time, seek to explore the non-canonical role of lens AQPs as peroxiporins or H2O2 transporters,
alongside the protective roles of Cxs and GPX1 in scavenging lenticular H2O2. Main Hypothesis is: Lens AQPs
transport extracellular H2O2 into epithelial and peripheral fiber cells, where it is detoxified by GSH/GPX1,
thus removing extracellular H2O2 from the circulation to central fiber cells, which have low GSH and no
GPX1. Age-induced reductions in the function of GPX1 cause H2O2-initiated damage to lens AQPs, Cxs
and Na+/K+-ATPase, thus compromising the microcirculation and contributing to ARC. To test, in Aim 1,
we will quantify age-related changes in transparency in relation to alteration in H2O2 transport by AQPs using the
lenses of WT and AQP-KO models. We will test if post-translationally end-cleaved AQP0s transport H2O2 and
are regulated by pH, calcium and zinc, using intact lenses of WT and a transgenic mouse model. We will
investigate whether the increase in H2O2 level during aging will alter the intracellular pH of the lens. In Aim 2, we
will explore the protective role of GPX1 on AQPs, Cxs and Na+/K+-ATPase to maintain the lens microcirculatory
system during aging, using WT and GPX1-KO lenses. We will test the spatial and temporal H2O2, and reduced
(GSH) and oxidized GSH (GSSG) levels in GPX1-KO in relation to ARC. In Aim 3, we intend to enhance GPX1
activity through a diet containing GPX1-mimic Ebselen in WT and GPX1-KO mice, to lessen GPX1-reduction-
induced H2O2 surge and adverse oxidative stress during aging. We believe that the emerging data as a funct...

## Key facts

- **NIH application ID:** 10521389
- **Project number:** 1R01EY033346-01A1
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Kulandaiappan Varadaraj
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $398,750
- **Award type:** 1
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10521389

## Citation

> US National Institutes of Health, RePORTER application 10521389, Roles of Lens Aquaporins and GPX1 in Hydrogen Peroxide Balance, Homeostasis, and Aging (1R01EY033346-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10521389. Licensed CC0.

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