Poly(ADP-ribose)polymerase inhibition counteracts cataract formation and early retinal changes in streptozotocin-diabetic rats

Viktor R. Drel, Weizheng Xu, Jie Zhang, Peter F Kador, Tayyeba K. Ali, Jeho Shin, Ulrich Julius, Barbara Slusher, Azza B. El-Remessy, Irina G. Obrosova

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Abstract

Purpose: This study evaluated the role for poly(ADP-ribose) polymerase (PARP) in diabetes-induced cataractogenesis and early retinal changes. Methods: Control and streptozotocin (STZ)-diabetic rats were treated with or without the PARP inhibitors 1,5-isoquinolinediol (ISO; 3 mg kg-1 d-1 intraperitoneally) and 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de]anthracen -3-1 (GPI-15427, 30 mg kg-1 d-1 orally) for 10 weeks after the first 2 weeks without treatment. Lens clarity was evaluated by indirect ophthalmoscopy and slit lamp examination, and retinal changes were evaluated by immunohistochemistry and Western blot analysis. In in vitro studies, cultured human lens epithelial cells and bovine retinal pericytes and endothelial cells were exposed to high glucose or palmitate. Results: PARP is expressed in lens, and poly(ADP-ribosyl)ated proteins are primarily localized in the 38- to 87-kDa range of the protein spectrum, with several minor bands at 17 to 38 kDa. The 38- to 87-kDa and the 17- to 38-kDa poly(ADP-ribosyl)ated protein expression increased by 74% and 275%, respectively, after 4 weeks of diabetes and by approximately 65% early after exposure of lens epithelial cells to 30 mM glucose. Both PARP inhibitors delayed, but did not prevent, the formation of diabetic cataract. The number of TUNEL-positive nuclei in flatmounted retinas increased approximately 4-fold in STZ diabetic rats, and this increase was prevented by ISO and GPI-15427. Both PARP inhibitors reduced diabetes-induced retinal oxidative-nitrosative and endoplasmic reticulum stress and glial activation. GPI-15427 (20 μM) prevented oxidative-nitrosative stress and cell death in palmitate-exposed pericytes and endothelial cells. Conclusions: PARP activation is implicated in the formation of diabetic cataract and in early retinal changes. These findings provide a rationale for the development of PARP inhibitors for the prevention of diabetic ocular complications.

Original languageEnglish (US)
Pages (from-to)1778-1790
Number of pages13
JournalInvestigative Ophthalmology and Visual Science
Volume50
Issue number4
DOIs
StatePublished - Apr 1 2009

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Poly(ADP-ribose) Polymerases
Streptozocin
Cataract
Lenses
Pericytes
Palmitates
Endothelial Cells
Epithelial Cells
Glucose
Ophthalmoscopy
Endoplasmic Reticulum Stress
In Situ Nick-End Labeling
Diabetes Complications
Neuroglia
Retina
Oxidative Stress
Cell Death
Western Blotting
Immunohistochemistry
Poly(ADP-ribose) Polymerase Inhibitors

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Poly(ADP-ribose)polymerase inhibition counteracts cataract formation and early retinal changes in streptozotocin-diabetic rats. / Drel, Viktor R.; Xu, Weizheng; Zhang, Jie; Kador, Peter F; Ali, Tayyeba K.; Shin, Jeho; Julius, Ulrich; Slusher, Barbara; El-Remessy, Azza B.; Obrosova, Irina G.

In: Investigative Ophthalmology and Visual Science, Vol. 50, No. 4, 01.04.2009, p. 1778-1790.

Research output: Contribution to journalArticle

Drel, Viktor R. ; Xu, Weizheng ; Zhang, Jie ; Kador, Peter F ; Ali, Tayyeba K. ; Shin, Jeho ; Julius, Ulrich ; Slusher, Barbara ; El-Remessy, Azza B. ; Obrosova, Irina G. / Poly(ADP-ribose)polymerase inhibition counteracts cataract formation and early retinal changes in streptozotocin-diabetic rats. In: Investigative Ophthalmology and Visual Science. 2009 ; Vol. 50, No. 4. pp. 1778-1790.
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abstract = "Purpose: This study evaluated the role for poly(ADP-ribose) polymerase (PARP) in diabetes-induced cataractogenesis and early retinal changes. Methods: Control and streptozotocin (STZ)-diabetic rats were treated with or without the PARP inhibitors 1,5-isoquinolinediol (ISO; 3 mg kg-1 d-1 intraperitoneally) and 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de]anthracen -3-1 (GPI-15427, 30 mg kg-1 d-1 orally) for 10 weeks after the first 2 weeks without treatment. Lens clarity was evaluated by indirect ophthalmoscopy and slit lamp examination, and retinal changes were evaluated by immunohistochemistry and Western blot analysis. In in vitro studies, cultured human lens epithelial cells and bovine retinal pericytes and endothelial cells were exposed to high glucose or palmitate. Results: PARP is expressed in lens, and poly(ADP-ribosyl)ated proteins are primarily localized in the 38- to 87-kDa range of the protein spectrum, with several minor bands at 17 to 38 kDa. The 38- to 87-kDa and the 17- to 38-kDa poly(ADP-ribosyl)ated protein expression increased by 74{\%} and 275{\%}, respectively, after 4 weeks of diabetes and by approximately 65{\%} early after exposure of lens epithelial cells to 30 mM glucose. Both PARP inhibitors delayed, but did not prevent, the formation of diabetic cataract. The number of TUNEL-positive nuclei in flatmounted retinas increased approximately 4-fold in STZ diabetic rats, and this increase was prevented by ISO and GPI-15427. Both PARP inhibitors reduced diabetes-induced retinal oxidative-nitrosative and endoplasmic reticulum stress and glial activation. GPI-15427 (20 μM) prevented oxidative-nitrosative stress and cell death in palmitate-exposed pericytes and endothelial cells. Conclusions: PARP activation is implicated in the formation of diabetic cataract and in early retinal changes. These findings provide a rationale for the development of PARP inhibitors for the prevention of diabetic ocular complications.",
author = "Drel, {Viktor R.} and Weizheng Xu and Jie Zhang and Kador, {Peter F} and Ali, {Tayyeba K.} and Jeho Shin and Ulrich Julius and Barbara Slusher and El-Remessy, {Azza B.} and Obrosova, {Irina G.}",
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AU - Drel, Viktor R.

AU - Xu, Weizheng

AU - Zhang, Jie

AU - Kador, Peter F

AU - Ali, Tayyeba K.

AU - Shin, Jeho

AU - Julius, Ulrich

AU - Slusher, Barbara

AU - El-Remessy, Azza B.

AU - Obrosova, Irina G.

PY - 2009/4/1

Y1 - 2009/4/1

N2 - Purpose: This study evaluated the role for poly(ADP-ribose) polymerase (PARP) in diabetes-induced cataractogenesis and early retinal changes. Methods: Control and streptozotocin (STZ)-diabetic rats were treated with or without the PARP inhibitors 1,5-isoquinolinediol (ISO; 3 mg kg-1 d-1 intraperitoneally) and 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de]anthracen -3-1 (GPI-15427, 30 mg kg-1 d-1 orally) for 10 weeks after the first 2 weeks without treatment. Lens clarity was evaluated by indirect ophthalmoscopy and slit lamp examination, and retinal changes were evaluated by immunohistochemistry and Western blot analysis. In in vitro studies, cultured human lens epithelial cells and bovine retinal pericytes and endothelial cells were exposed to high glucose or palmitate. Results: PARP is expressed in lens, and poly(ADP-ribosyl)ated proteins are primarily localized in the 38- to 87-kDa range of the protein spectrum, with several minor bands at 17 to 38 kDa. The 38- to 87-kDa and the 17- to 38-kDa poly(ADP-ribosyl)ated protein expression increased by 74% and 275%, respectively, after 4 weeks of diabetes and by approximately 65% early after exposure of lens epithelial cells to 30 mM glucose. Both PARP inhibitors delayed, but did not prevent, the formation of diabetic cataract. The number of TUNEL-positive nuclei in flatmounted retinas increased approximately 4-fold in STZ diabetic rats, and this increase was prevented by ISO and GPI-15427. Both PARP inhibitors reduced diabetes-induced retinal oxidative-nitrosative and endoplasmic reticulum stress and glial activation. GPI-15427 (20 μM) prevented oxidative-nitrosative stress and cell death in palmitate-exposed pericytes and endothelial cells. Conclusions: PARP activation is implicated in the formation of diabetic cataract and in early retinal changes. These findings provide a rationale for the development of PARP inhibitors for the prevention of diabetic ocular complications.

AB - Purpose: This study evaluated the role for poly(ADP-ribose) polymerase (PARP) in diabetes-induced cataractogenesis and early retinal changes. Methods: Control and streptozotocin (STZ)-diabetic rats were treated with or without the PARP inhibitors 1,5-isoquinolinediol (ISO; 3 mg kg-1 d-1 intraperitoneally) and 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de]anthracen -3-1 (GPI-15427, 30 mg kg-1 d-1 orally) for 10 weeks after the first 2 weeks without treatment. Lens clarity was evaluated by indirect ophthalmoscopy and slit lamp examination, and retinal changes were evaluated by immunohistochemistry and Western blot analysis. In in vitro studies, cultured human lens epithelial cells and bovine retinal pericytes and endothelial cells were exposed to high glucose or palmitate. Results: PARP is expressed in lens, and poly(ADP-ribosyl)ated proteins are primarily localized in the 38- to 87-kDa range of the protein spectrum, with several minor bands at 17 to 38 kDa. The 38- to 87-kDa and the 17- to 38-kDa poly(ADP-ribosyl)ated protein expression increased by 74% and 275%, respectively, after 4 weeks of diabetes and by approximately 65% early after exposure of lens epithelial cells to 30 mM glucose. Both PARP inhibitors delayed, but did not prevent, the formation of diabetic cataract. The number of TUNEL-positive nuclei in flatmounted retinas increased approximately 4-fold in STZ diabetic rats, and this increase was prevented by ISO and GPI-15427. Both PARP inhibitors reduced diabetes-induced retinal oxidative-nitrosative and endoplasmic reticulum stress and glial activation. GPI-15427 (20 μM) prevented oxidative-nitrosative stress and cell death in palmitate-exposed pericytes and endothelial cells. Conclusions: PARP activation is implicated in the formation of diabetic cataract and in early retinal changes. These findings provide a rationale for the development of PARP inhibitors for the prevention of diabetic ocular complications.

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