Deletion of the Akt/mTORC1 repressor REDD1 prevents visual dysfunction in a rodent model of type 1 diabetes

William P. Miller, Chen Yang, Maria L. Mihailescu, Joshua A. Moore, Weiwei Dai, Alistair J. Barber, Michael D. Dennis

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Diabetes-induced visual dysfunction is associated with significant neuroretinal cell death. The current study was designed to investigate the role of the Protein Regulated in Development and DNA Damage Response 1 (REDD1) in diabetes-induced retinal cell death and visual dysfunction. We recently demonstrated that REDD1 protein expression was elevated in response to hyperglycemia in the retina of diabetic rodents. REDD1 is an important regulator of Akt and mammalian target of rapamycin and as such plays a key role in neuronal function and survival. In R28 retinal cells in culture, hyperglycemic conditions enhanced REDD1 protein expression concomitant with caspase activation and cell death. By contrast, in REDD1-deficient R28 cells, neither hyperglycemic conditions nor the absence of insulin in culture medium were sufficient to promote cell death. In the retinas of streptozotocin-induced diabetic mice, retinal apoptosis was dramatically elevated compared with nondiabetic controls, whereas no difference was observed in diabetic and nondiabetic REDD1-deficient mice. Electroretinogram abnormalities observed in b-wave and oscillatory potentials of diabetic wild-type mice were also absent in REDD1-deficient mice. Moreover, diabetic wild-type mice exhibited functional deficiencies in visual acuity and contrast sensitivity, whereas diabetic REDD1-deficient mice had no visual dysfunction. The results support a role for REDD1 in diabetes-induced retinal neurodegeneration.

Original languageEnglish (US)
Pages (from-to)110-119
Number of pages10
JournalDiabetes
Volume67
Issue number1
DOIs
StatePublished - Jan 1 2018

Fingerprint

Type 1 Diabetes Mellitus
Rodentia
Cell Death
Retina
Contrast Sensitivity
Proteins
Sirolimus
Streptozocin
Caspases
Hyperglycemia
Visual Acuity
DNA Damage
Culture Media
mechanistic target of rapamycin complex 1
Cell Culture Techniques
Insulin
Apoptosis

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Miller, William P. ; Yang, Chen ; Mihailescu, Maria L. ; Moore, Joshua A. ; Dai, Weiwei ; Barber, Alistair J. ; Dennis, Michael D. / Deletion of the Akt/mTORC1 repressor REDD1 prevents visual dysfunction in a rodent model of type 1 diabetes. In: Diabetes. 2018 ; Vol. 67, No. 1. pp. 110-119.
@article{f3168fb864c24864a77eecc053947f4a,
title = "Deletion of the Akt/mTORC1 repressor REDD1 prevents visual dysfunction in a rodent model of type 1 diabetes",
abstract = "Diabetes-induced visual dysfunction is associated with significant neuroretinal cell death. The current study was designed to investigate the role of the Protein Regulated in Development and DNA Damage Response 1 (REDD1) in diabetes-induced retinal cell death and visual dysfunction. We recently demonstrated that REDD1 protein expression was elevated in response to hyperglycemia in the retina of diabetic rodents. REDD1 is an important regulator of Akt and mammalian target of rapamycin and as such plays a key role in neuronal function and survival. In R28 retinal cells in culture, hyperglycemic conditions enhanced REDD1 protein expression concomitant with caspase activation and cell death. By contrast, in REDD1-deficient R28 cells, neither hyperglycemic conditions nor the absence of insulin in culture medium were sufficient to promote cell death. In the retinas of streptozotocin-induced diabetic mice, retinal apoptosis was dramatically elevated compared with nondiabetic controls, whereas no difference was observed in diabetic and nondiabetic REDD1-deficient mice. Electroretinogram abnormalities observed in b-wave and oscillatory potentials of diabetic wild-type mice were also absent in REDD1-deficient mice. Moreover, diabetic wild-type mice exhibited functional deficiencies in visual acuity and contrast sensitivity, whereas diabetic REDD1-deficient mice had no visual dysfunction. The results support a role for REDD1 in diabetes-induced retinal neurodegeneration.",
author = "Miller, {William P.} and Chen Yang and Mihailescu, {Maria L.} and Moore, {Joshua A.} and Weiwei Dai and Barber, {Alistair J.} and Dennis, {Michael D.}",
year = "2018",
month = "1",
day = "1",
doi = "10.2337/db17-0728",
language = "English (US)",
volume = "67",
pages = "110--119",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "1",

}

Deletion of the Akt/mTORC1 repressor REDD1 prevents visual dysfunction in a rodent model of type 1 diabetes. / Miller, William P.; Yang, Chen; Mihailescu, Maria L.; Moore, Joshua A.; Dai, Weiwei; Barber, Alistair J.; Dennis, Michael D.

In: Diabetes, Vol. 67, No. 1, 01.01.2018, p. 110-119.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Deletion of the Akt/mTORC1 repressor REDD1 prevents visual dysfunction in a rodent model of type 1 diabetes

AU - Miller, William P.

AU - Yang, Chen

AU - Mihailescu, Maria L.

AU - Moore, Joshua A.

AU - Dai, Weiwei

AU - Barber, Alistair J.

AU - Dennis, Michael D.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Diabetes-induced visual dysfunction is associated with significant neuroretinal cell death. The current study was designed to investigate the role of the Protein Regulated in Development and DNA Damage Response 1 (REDD1) in diabetes-induced retinal cell death and visual dysfunction. We recently demonstrated that REDD1 protein expression was elevated in response to hyperglycemia in the retina of diabetic rodents. REDD1 is an important regulator of Akt and mammalian target of rapamycin and as such plays a key role in neuronal function and survival. In R28 retinal cells in culture, hyperglycemic conditions enhanced REDD1 protein expression concomitant with caspase activation and cell death. By contrast, in REDD1-deficient R28 cells, neither hyperglycemic conditions nor the absence of insulin in culture medium were sufficient to promote cell death. In the retinas of streptozotocin-induced diabetic mice, retinal apoptosis was dramatically elevated compared with nondiabetic controls, whereas no difference was observed in diabetic and nondiabetic REDD1-deficient mice. Electroretinogram abnormalities observed in b-wave and oscillatory potentials of diabetic wild-type mice were also absent in REDD1-deficient mice. Moreover, diabetic wild-type mice exhibited functional deficiencies in visual acuity and contrast sensitivity, whereas diabetic REDD1-deficient mice had no visual dysfunction. The results support a role for REDD1 in diabetes-induced retinal neurodegeneration.

AB - Diabetes-induced visual dysfunction is associated with significant neuroretinal cell death. The current study was designed to investigate the role of the Protein Regulated in Development and DNA Damage Response 1 (REDD1) in diabetes-induced retinal cell death and visual dysfunction. We recently demonstrated that REDD1 protein expression was elevated in response to hyperglycemia in the retina of diabetic rodents. REDD1 is an important regulator of Akt and mammalian target of rapamycin and as such plays a key role in neuronal function and survival. In R28 retinal cells in culture, hyperglycemic conditions enhanced REDD1 protein expression concomitant with caspase activation and cell death. By contrast, in REDD1-deficient R28 cells, neither hyperglycemic conditions nor the absence of insulin in culture medium were sufficient to promote cell death. In the retinas of streptozotocin-induced diabetic mice, retinal apoptosis was dramatically elevated compared with nondiabetic controls, whereas no difference was observed in diabetic and nondiabetic REDD1-deficient mice. Electroretinogram abnormalities observed in b-wave and oscillatory potentials of diabetic wild-type mice were also absent in REDD1-deficient mice. Moreover, diabetic wild-type mice exhibited functional deficiencies in visual acuity and contrast sensitivity, whereas diabetic REDD1-deficient mice had no visual dysfunction. The results support a role for REDD1 in diabetes-induced retinal neurodegeneration.

UR - http://www.scopus.com/inward/record.url?scp=85038965805&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85038965805&partnerID=8YFLogxK

U2 - 10.2337/db17-0728

DO - 10.2337/db17-0728

M3 - Article

C2 - 29074598

AN - SCOPUS:85038965805

VL - 67

SP - 110

EP - 119

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 1

ER -