Novel transgenic mouse models develop retinal changes associated with early diabetic retinopathy similar to those observed in rats with diabetes mellitus

Changmei Guo, Zifeng Zhang, Peng Zhang, Jun Makita, Hiroyoshi Kawada, Karen Blessing, Peter F Kador

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Retinal capillary pericyte degeneration has been linked to aldose reductase (AR) activity in diabetic retinopathy (DR). Since the development of DR in mice and rats has been reported to differ and that this may be linked to differences in retinal sorbitol levels, we have established new murine models of early onset diabetes mellitus as tools for investigating the role of AR in DR. Transgenic diabetic mouse models were developed by crossbreeding diabetic C57BL/6-Ins2 Akita /J (AK) with transgenic C57BL mice expressing green fluorescent protein (GFP), human aldose reductase (hAR) or both in vascular tissues containing smooth muscle actin-α (SMAA). Changes in retinal sorbitol levels were determined by HPLC while changes of growth factors and signaling were investigated by Western Blots. Retinal vascular changes were quantitatively analyzed on elastase-digestion flat mounts. Results show that sorbitol levels were higher in neural retinas of diabetic AK-SMAA-GFP-hAR compared to AK-SMAA-GFP mice. AK-SMAA-GFP-hAR mice showed induction of the retinal growth factors VEGF, IGF-1, bFGF and TGFβ, as well as signaling changes in P-Akt, P-SAPK/JNK, and P-44/42 MAPK. Increased loss of nuclei per capillary length and a significant increase in the percentage of acellular capillaries presented in 18 week old AK-SMAA-GFP-hAR mice. These changes are similar to those observed in streptozotocin-induced diabetic rats. Retinal changes in both mice and rats were prevented by inhibition of AR. These studies confirm that the increased expression of AR in mice results in the development of retinal changes associated with the early stages of DR that are similar to those observed in rats.

Original languageEnglish (US)
Pages (from-to)77-87
Number of pages11
JournalExperimental Eye Research
Volume119
DOIs
StatePublished - Feb 1 2014

Fingerprint

Aldehyde Reductase
Diabetic Retinopathy
Transgenic Mice
Diabetes Mellitus
Green Fluorescent Proteins
Sorbitol
Intercellular Signaling Peptides and Proteins
Genetic Hybridization
Retinal Vessels
Pericytes
Pancreatic Elastase
Streptozocin
Insulin-Like Growth Factor I
Inbred C57BL Mouse
Vascular Endothelial Growth Factor A
Smooth Muscle
Blood Vessels
Retina
Actins
Digestion

Keywords

  • Aldose reductase
  • Cell signaling P-ERK1/2, P-SAPK/JNK, P-Akt
  • Diabetic rats
  • Diabetic retinopathy
  • Green fluorescent proteins
  • Growth factors VEGF, bFGF, TGF-β
  • Retinal vascular changes
  • Transgenic diabetic mouse models

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Novel transgenic mouse models develop retinal changes associated with early diabetic retinopathy similar to those observed in rats with diabetes mellitus. / Guo, Changmei; Zhang, Zifeng; Zhang, Peng; Makita, Jun; Kawada, Hiroyoshi; Blessing, Karen; Kador, Peter F.

In: Experimental Eye Research, Vol. 119, 01.02.2014, p. 77-87.

Research output: Contribution to journalArticle

Guo, Changmei ; Zhang, Zifeng ; Zhang, Peng ; Makita, Jun ; Kawada, Hiroyoshi ; Blessing, Karen ; Kador, Peter F. / Novel transgenic mouse models develop retinal changes associated with early diabetic retinopathy similar to those observed in rats with diabetes mellitus. In: Experimental Eye Research. 2014 ; Vol. 119. pp. 77-87.
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abstract = "Retinal capillary pericyte degeneration has been linked to aldose reductase (AR) activity in diabetic retinopathy (DR). Since the development of DR in mice and rats has been reported to differ and that this may be linked to differences in retinal sorbitol levels, we have established new murine models of early onset diabetes mellitus as tools for investigating the role of AR in DR. Transgenic diabetic mouse models were developed by crossbreeding diabetic C57BL/6-Ins2 Akita /J (AK) with transgenic C57BL mice expressing green fluorescent protein (GFP), human aldose reductase (hAR) or both in vascular tissues containing smooth muscle actin-α (SMAA). Changes in retinal sorbitol levels were determined by HPLC while changes of growth factors and signaling were investigated by Western Blots. Retinal vascular changes were quantitatively analyzed on elastase-digestion flat mounts. Results show that sorbitol levels were higher in neural retinas of diabetic AK-SMAA-GFP-hAR compared to AK-SMAA-GFP mice. AK-SMAA-GFP-hAR mice showed induction of the retinal growth factors VEGF, IGF-1, bFGF and TGFβ, as well as signaling changes in P-Akt, P-SAPK/JNK, and P-44/42 MAPK. Increased loss of nuclei per capillary length and a significant increase in the percentage of acellular capillaries presented in 18 week old AK-SMAA-GFP-hAR mice. These changes are similar to those observed in streptozotocin-induced diabetic rats. Retinal changes in both mice and rats were prevented by inhibition of AR. These studies confirm that the increased expression of AR in mice results in the development of retinal changes associated with the early stages of DR that are similar to those observed in rats.",
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KW - Transgenic diabetic mouse models

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