title: Diabetic retinopathy is associated with bone marrow neuropathy and a depressed peripheral clock.
abstract: The present epidemic of diabetes is resulting in a worldwide increase in cardiovascular and microvascular complications including retinopathy. Current thinking has focused on local influences in the retina as being responsible for development of this diabetic complication. However, the contribution of circulating cells in maintenance, repair, and dysfunction of the vasculature is now becoming appreciated. Diabetic individuals have fewer endothelial progenitor cells (EPCs) in their circulation and these cells have diminished migratory potential, which contributes to their decreased reparative capacity. Using a rat model of type 2 diabetes, we show that the decrease in EPC release from diabetic bone marrow is caused by bone marrow neuropathy and that these changes precede the development of diabetic retinopathy. In rats that had diabetes for 4 mo, we observed a dramatic reduction in the number of nerve terminal endings in the bone marrow. Denervation was accompanied by increased numbers of EPCs within the bone marrow but decreased numbers in circulation. Furthermore, denervation was accompanied by a loss of circadian release of EPCs and a marked reduction in clock gene expression in the retina and in EPCs themselves. This reduction in the circadian peak of EPC release led to diminished reparative capacity, resulting in the development of the hallmark feature of diabetic retinopathy, acellular retinal capillaries. Thus, for the first time, diabetic retinopathy is related to neuropathy of the bone marrow. This novel finding shows that bone marrow denervation represents a new therapeutic target for treatment of diabetic vascular complications.
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI 48824, USA. busik@msu.edu
authors.forename: Julia V
authors.initials: JV
authors.lastname: Busik
authors.forename: Maria
authors.initials: M
authors.lastname: Tikhonenko
authors.forename: Ashay
authors.initials: A
authors.lastname: Bhatwadekar
authors.forename: Madalina
authors.initials: M
authors.lastname: Opreanu
authors.forename: Nafissa
authors.initials: N
authors.lastname: Yakubova
authors.forename: Sergio
authors.initials: S
authors.lastname: Caballero
authors.forename: Danny
authors.initials: D
authors.lastname: Player
authors.forename: Takahiko
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Aqeela
authors.initials: A
authors.lastname: Afzal
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kielczewski
authors.forename: Andrew
authors.initials: A
authors.lastname: Sochacki
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hasty
authors.forename: Sergio
authors.initials: S
authors.lastname: Li Calzi
authors.forename: Sungjin
authors.initials: S
authors.lastname: Kim
authors.forename: Shane K
authors.initials: SK
authors.lastname: Duclas
authors.forename: Mark S
authors.initials: MS
authors.lastname: Segal
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Guberski
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Esselman
authors.forename: Michael E
authors.initials: ME
authors.lastname: Boulton
authors.forename: Maria B
authors.initials: MB
authors.lastname: Grant
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000294:innervation*; D056926:CLOCK Proteins / Q000235:genetics*; D002940:Circadian Rhythm; D003714:Denervation; D003929:Diabetic Neuropathies / Q000150:complications*; D003930:Diabetic Retinopathy / Q000209:etiology*; D005260:Female; D006412:Hematopoietic Stem Cells / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009638:Norepinephrine / Q000097:blood; D051381:Rats; D013564:Sympathetic Nervous System / Q000502:physiology
chemical_list: D056926:CLOCK Proteins; D009638:Norepinephrine