TY - JOUR
T1 - Combined SIRT3 and SIRT5 deletion is associated with inner retinal dysfunction in a mouse model of type 1 diabetes
AU - Lin, Jonathan B.
AU - Lin, Joseph B.
AU - Chen, Howard C.
AU - Chen, Teresa
AU - Apte, Rajendra S.
N1 - Funding Information:
This work was supported by NIH Grants R01 EY019287 (R.S.A.) and P30 EY02687 (Vision Core Grant); the Starr Foundation (R.S.A.); the Carl Marshall Reeves and Mildred Almen Reeves Foundation (R.S.A.); the Bill and Emily Kuzma Family Gift for retinal research (R.S.A.); a Physician-Scientist Award and a Nelson Trust Award from Research to Prevent Blindness (R.S.A.); the Jeffrey Fort Innovation Fund (R.S.A.); the Glenn Foundation (R.S.A.); and the Thome Foundation (R.S.A.). Additional funding comes from an unrestricted grant to the Department of Ophthalmology and Visual Sciences of Washington University School of Medicine from Research to Prevent Blindness. Jonathan B. Lin was supported by the Washington University in St. Louis Medical Scientist Training Program (NIH Grant T32 GM07200) and the Washington University in St. Louis Institute of Clinical and Translational Sciences (NIH Grants UL1 TR002345, TL1 TR002344). Joseph B. Lin was supported by NIH Grant T32 GM07200. We thank Gregory Bligard for help with ERG analysis.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Diabetic retinopathy (DR) is a major cause of blindness in working adults in the industrialized world. In addition to vision loss caused by macular edema and pathological angiogenesis, DR patients often exhibit neuronal dysfunction on electrophysiological testing, suggesting that there may be an independent neuronal phase of disease that precedes vascular disease. Given the tremendous metabolic requirements of the retina and photoreceptors in particular, we hypothesized that derangements in metabolic regulation may accelerate retinal dysfunction in diabetes. As such, we induced hyperglycemia with streptozotocin in mice with monoallelic Nampt deletion from rod photoreceptors, mice lacking SIRT3, and mice lacking SIRT5 and tested multiple components of retinal function with electroretinography. None of these mice exhibited accelerated retinal dysfunction after induction of hyperglycemia, consistent with normal-appearing retinal morphology in hyperglycemic Sirt3 −/− or Sirt5 −/− mice. However, mice lacking both SIRT3 and SIRT5 (Sirt3 −/− Sirt5 −/− mice) exhibited significant evidence of inner retinal dysfunction after induction of hyperglycemia compared to hyperglycemic littermate controls, although this dysfunction was not accompanied by gross morphological changes in the retina. These results suggest that SIRT3 and SIRT5 may be involved in regulating neuronal dysfunction in DR and provide a foundation for future studies investigating sirtuin-based therapies.
AB - Diabetic retinopathy (DR) is a major cause of blindness in working adults in the industrialized world. In addition to vision loss caused by macular edema and pathological angiogenesis, DR patients often exhibit neuronal dysfunction on electrophysiological testing, suggesting that there may be an independent neuronal phase of disease that precedes vascular disease. Given the tremendous metabolic requirements of the retina and photoreceptors in particular, we hypothesized that derangements in metabolic regulation may accelerate retinal dysfunction in diabetes. As such, we induced hyperglycemia with streptozotocin in mice with monoallelic Nampt deletion from rod photoreceptors, mice lacking SIRT3, and mice lacking SIRT5 and tested multiple components of retinal function with electroretinography. None of these mice exhibited accelerated retinal dysfunction after induction of hyperglycemia, consistent with normal-appearing retinal morphology in hyperglycemic Sirt3 −/− or Sirt5 −/− mice. However, mice lacking both SIRT3 and SIRT5 (Sirt3 −/− Sirt5 −/− mice) exhibited significant evidence of inner retinal dysfunction after induction of hyperglycemia compared to hyperglycemic littermate controls, although this dysfunction was not accompanied by gross morphological changes in the retina. These results suggest that SIRT3 and SIRT5 may be involved in regulating neuronal dysfunction in DR and provide a foundation for future studies investigating sirtuin-based therapies.
UR - http://www.scopus.com/inward/record.url?scp=85062608508&partnerID=8YFLogxK
U2 - 10.1038/s41598-019-40177-6
DO - 10.1038/s41598-019-40177-6
M3 - Article
C2 - 30846716
AN - SCOPUS:85062608508
SN - 2045-2322
VL - 9
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 3799
ER -