Renu A Kowluru1, Manish Mishra2, Anjaneyulu Kowluru3, Binit Kumar2. 1. Ophthalmology, Wayne State University, Detroit, MI, United States. Electronic address: rkowluru@med.wayne.edu. 2. Ophthalmology, Wayne State University, Detroit, MI, United States. 3. Pharmaceutical Sciences, Wayne State University, Detroit, MI, United States; John D. Dingell VA Medical Center, Detroit, MI, United States.
Abstract
AIM: In the pathogenesis of diabetic retinopathy, reactive oxygen species (ROS) are elevated in the retina and the mitochondria are damaged, resulting in accelerated apoptosis. Dyslipidemia is also considered as one of the major factors in its development, and our aim is to investigate the compounding effect of hyperlipidemia in retinopathy. METHODS: Retinal ROS, mitochondrial damage and vascular pathology were investigated in Zucker diabetic fatty rats (ZDF, type 2 diabetes model), during the age that spans from hyperlipidemia/pre-hyperglycemia (6weeks), to severe hyperglycemia/moderate hyperlipidemia (~12weeks), and ultimately to severe hyperglycemia/hyperlipidemia (20-40weeks). For comparison, retina from streptozotocin-induced Wistar rats (type 1 diabetic for 10-40weeks) was analyzed. RESULTS: Compared to age-matched lean rats, despite increased retinal cytosolic ROS in 6-week-old ZDF rats, mitochondrial dysfunction and DNA damage were not detected, and in 12-week-old ZDF rats, retinal mitochondria were dysfunctional, but mtDNA damage and vascular pathology (cell apoptosis and degenerative capillaries) were not detectable. Retina from 20-week-old ZDF rats (hyperglycemic for 14weeks or less) had significant mitochondrial dysfunction, mtDNA damage and vascular pathology, and similar abnormalities were observed in 40-week-old ZDF rats. Although retinal mitochondrial dysfunction was observed in Wistar rats diabetic for 20weeks, mtDNA damage and vascular pathology were not detectable till the duration of diabetes was further extended. CONCLUSIONS: Hyperlipidemia, in a hyperglycemic milieu, potentiates mitochondrial damage and augments the development of retinopathy. Control of dyslipidemia in pre-diabetic patients may prevent/delay the development and the progression of this devastating disease.
AIM: In the pathogenesis of diabetic retinopathy, reactive oxygen species (ROS) are elevated in the retina and the mitochondria are damaged, resulting in accelerated apoptosis. Dyslipidemia is also considered as one of the major factors in its development, and our aim is to investigate the compounding effect of hyperlipidemia in retinopathy. METHODS: Retinal ROS, mitochondrial damage and vascular pathology were investigated in Zucker diabetic fattyrats (ZDF, type 2 diabetes model), during the age that spans from hyperlipidemia/pre-hyperglycemia (6weeks), to severe hyperglycemia/moderate hyperlipidemia (~12weeks), and ultimately to severe hyperglycemia/hyperlipidemia (20-40weeks). For comparison, retina from streptozotocin-induced Wistar rats (type 1 diabetic for 10-40weeks) was analyzed. RESULTS: Compared to age-matched lean rats, despite increased retinal cytosolic ROS in 6-week-old ZDFrats, mitochondrial dysfunction and DNA damage were not detected, and in 12-week-old ZDFrats, retinal mitochondria were dysfunctional, but mtDNA damage and vascular pathology (cell apoptosis and degenerative capillaries) were not detectable. Retina from 20-week-old ZDFrats (hyperglycemic for 14weeks or less) had significant mitochondrial dysfunction, mtDNA damage and vascular pathology, and similar abnormalities were observed in 40-week-old ZDFrats. Although retinal mitochondrial dysfunction was observed in Wistar ratsdiabetic for 20weeks, mtDNA damage and vascular pathology were not detectable till the duration of diabetes was further extended. CONCLUSIONS:Hyperlipidemia, in a hyperglycemic milieu, potentiates mitochondrial damage and augments the development of retinopathy. Control of dyslipidemia in pre-diabeticpatients may prevent/delay the development and the progression of this devastating disease.
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