Per2 Mutation Recapitulates the Vascular Phenotype of Diabetes in the Retina and Bone Marrow
- Ashay D. Bhatwadekar1,
- Yuanqing Yan1,
- Xiaoping Qi2,
- Jeffrey S. Thinschmidt1,
- Matthew B. Neu1,
- Sergio Li Calzi1,
- Lynn C. Shaw1,
- James M. Dominiguez1,
- Julia V. Busik3,
- Choogon Lee4,
- Michael E. Boulton2 and
- Maria B. Grant1⇓
- 1Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida
- 2Department of Anatomy and Cell Biology, University of Florida, Gainesville, Florida
- 3Department of Physiology, Michigan State University, East Lansing, Michigan
- 4Biomedical Sciences Department, Florida State University, Tallahassee, Florida
- Corresponding author: Maria B. Grant, grantma@.ufl.edu.
In this study, we assessed whether Per2 clock gene–mutant mice exhibit a vascular phenotype similar to diabetes. Per2 (B6.129-Per2tm1Drw/J) or wild-type control mice 4 and 12 months of age were used. To evaluate diabetes-like phenotype in Per2 mutant mice, retina was quantified for mRNA expression, and degree of diabetic retinopathy was evaluated. Bone marrow neuropathy was studied by staining femurs for tyrosine hydroxylase (TH) and neurofilament 200 (NF-200). The rate of proliferation and quantification of bone marrow progenitor cells (BMPCs) was performed, and a threefold decrease in proliferation and 50% reduction in nitric oxide levels were observed in Per2 mutant mice. TH-positive nerve processes and NF-200 staining were reduced in Per2 mutant mice. Both retinal protein and mRNA expression of endothelial nitric oxide synthase were decreased by twofold. Other endothelial function genes (VEGFR2, VEGFR1) were downregulated (1.5–2-fold) in Per2 mutant retinas, whereas there was an upregulation of profibrotic pathway mediated by transforming growth factor-β1. Our studies suggest that Per2 mutant mice recapitulate key aspects of diabetes without the metabolic abnormalities, including retinal vascular damage, neuronal loss in the bone marrow, and diminished BMPC function.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-0172/-/DC1.
See accompanying commentary, p. 29.
- Received February 17, 2012.
- Accepted July 16, 2012.
- © 2013 by the American Diabetes Association.
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