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Pentosan Polysulfate Sodium Causes Diminished Function and Subtle Morphological Changes in Retina and RPE of Mice
Preston E Girardot1,2, Xian Zhang1,3, Nan Zhang1,4
1Department of Ophthalmology, Emory University, Atlanta, GA, United States.
Purpose:
There are numerous reports of a distinctive maculopathy in adults exposed to pentosan polysulfate sodium (PPS), a drug prescribed to treat bladder discomfort associated with interstitial cystitis. We tested whether PPS treatment of mice injures RPE or retina to provide insight into the etiology of the human condition.
Methods:
Mice were fed PPS-supplemented chow over 14 months. RPE and retinal function was assessed by electroretinography (ERG) regularly. Following euthanasia, one eye was used for sagittal sectioning and histology, the contralateral for RPE flatmounting. ZO-1 positive RPE cell borders were imaged using confocal microscopy and cell morphology was analyzed using CellProfiler.
Results:
After 10 months of PPS treatment, we observed diminution of mean scotopic c-wave amplitudes. By 11 months, we additionally observed diminutions of mean scotopic a- and b-wave amplitudes. Analysis of flatmounts revealed altered RPE cell morphology and morphometrics in PPS-treated mice, including increased mean en face cell area and geometric eccentricity, decreased RPE cell solidity and extent, and cytosolic translocation of alpha-catenin, all markers of RPE cell stress. Sex and regional differences were seen in RPE flatmount measures. Shortened photoreceptor outer segments were also observed.
Conclusions:
PPS treatment reduced RPE and later retina function as measured by ERG, consistent with a primary RPE injury. Post-mortem analysis revealed extensive RPE pleomorphism and polymegathism and modest photoreceptor changes. We conclude that PPS treatment of mice causes slowly progressing RPE and photoreceptor damage and thus may provide a useful model for some retinal pathologies.
Insights
Pentosan polysulfate sodium (PPS) treatment in mice caused retinal pigment epithelium (RPE) and photoreceptor damage, mimicking human maculopathy. This study offers a potential animal model for retinal pathologies linked to PPS exposure.
Area of Science:
- Ophthalmology
- Toxicology
- Cell Biology
Background:
- Pentosan polysulfate sodium (PPS) is prescribed for interstitial cystitis.
- Distinctive maculopathy has been reported in humans using PPS.
- The etiology of PPS-induced maculopathy remains unclear.
Purpose of the Study:
- To investigate if PPS treatment induces retinal pigment epithelium (RPE) or retinal injury in mice.
- To establish an animal model for understanding human PPS-associated maculopathy.
Main Methods:
- Mice received PPS-supplemented chow for 14 months.
- Retinal function was assessed using electroretinography (ERG).
- Histology and RPE flatmounts were analyzed for cellular morphology and stress markers.
Main Results:
- ERG showed reduced scotopic a-, b-, and c-wave amplitudes after 10-11 months of PPS treatment.
- RPE flatmount analysis revealed increased cell area, altered shape, decreased solidity, and alpha-catenin translocation, indicating RPE cell stress.
- Photoreceptor outer segments were shortened in PPS-treated mice.
Conclusions:
- PPS treatment progressively impairs RPE and retinal function in mice.
- Histological findings indicate primary RPE injury with secondary photoreceptor damage.
- This mouse model may be valuable for studying retinal pathologies associated with PPS exposure.
