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Exendin-4 protects retinal cells from early diabetes in Goto-Kakizaki rats by increasing the Bcl-2/Bax and Bcl-xL/Bax ratios and reducing reactive gliosis.

Fan Y, Liu K, Wang Q, Ruan Y, Zhang Y, Ye W - Mol. Vis. (2014)

Bottom Line: It also downregulated the expression of glial fibrillary acidic protein and reduced retinal reactive gliosis.Similar results were found in primary rat Müller cells under high glucose culture in vitro.E4 may protect retinal cells from diabetic attacks by activating GLP-1R, decreasing retinal cell apoptosis, and reducing retinal reactive gliosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Huashan Hospital Affiliated to Fudan University, Shanghai, China.

ABSTRACT

Purpose: Exendin-4 (E4), a long-acting agonist of the hormone glucagon-like peptide 1 receptor (GLP-1R), is administered to treat type II diabetes in the clinical setting and also shows a neuroprotective effect. Our previous studies demonstrated its protective effect in early experimental diabetic retinopathy (DR), but the molecular and cellular mechanisms are largely unknown. This study aimed to investigate the protective mechanism of a GLP-1R agonist E4 against early DR in Goto-Kakizaki (GK) rats.

Methods: Diabetic GK rats and control animals were randomly assigned to receive E4 or vehicle by intravitreal injection. The retinal function and retinal cell counts were evaluated using an electroretinogram and light microscopy. The expressions of retinal GLP-1R, mitochondria-dependent apoptosis-associated genes, reactive gliosis markers, and endoplasmic reticulum stress-related pathway genes were studied by western blotting and immunohistochemistry in vivo and in vitro.

Results: E4 significantly prevented the reduction of the b-wave and oscillatory potential amplitudes and retinal cell loss and maintained the Bcl-2/Bax and Bcl-xL/Bax ratio balances in GK rats. It also downregulated the expression of glial fibrillary acidic protein and reduced retinal reactive gliosis. Similar results were found in primary rat Müller cells under high glucose culture in vitro.

Conclusions: E4 may protect retinal cells from diabetic attacks by activating GLP-1R, decreasing retinal cell apoptosis, and reducing retinal reactive gliosis. Thus, E4 treatment may be a novel approach for early DR.

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Related in: MedlinePlus

No influence on the blood glucose level or bodyweight of GK rats by E4 treatment. Non-fasting blood glucose (A), fasting blood glucose (B) and bodyweight (C) of rats with and without E4 intravitreal injection at 12 weeks of age (two-way repeated ANOVA for interaction: non-fasting blood glucose, F(16,243)=1.112, p=0.344; fasting blood glucose, F(16,243)=1.157, p=0.304; bodyweight, F(16,243)=1.336, p=0.176; n=10). Bodyweight and non-fasting and fasting blood glucose levels did not statistically differ between the GK control and E4-treated group from 12 to 16 weeks of age (two-way ANOVA followed by Bonferroni’s test: non-fasting blood glucose, p=0.43; fasting blood glucose, p=0.921; bodyweight, p=0.576; n=10). Each datum point is expressed as the means ± SEM (n=10). GK rat: Goto-Kakizaki rat; E4: Exendin-4; Control: Wistar rats treated with sham injection (normal saline); G+NS: GK rats treated with normal saline; G+E4: GK rats treated with E4.
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f1: No influence on the blood glucose level or bodyweight of GK rats by E4 treatment. Non-fasting blood glucose (A), fasting blood glucose (B) and bodyweight (C) of rats with and without E4 intravitreal injection at 12 weeks of age (two-way repeated ANOVA for interaction: non-fasting blood glucose, F(16,243)=1.112, p=0.344; fasting blood glucose, F(16,243)=1.157, p=0.304; bodyweight, F(16,243)=1.336, p=0.176; n=10). Bodyweight and non-fasting and fasting blood glucose levels did not statistically differ between the GK control and E4-treated group from 12 to 16 weeks of age (two-way ANOVA followed by Bonferroni’s test: non-fasting blood glucose, p=0.43; fasting blood glucose, p=0.921; bodyweight, p=0.576; n=10). Each datum point is expressed as the means ± SEM (n=10). GK rat: Goto-Kakizaki rat; E4: Exendin-4; Control: Wistar rats treated with sham injection (normal saline); G+NS: GK rats treated with normal saline; G+E4: GK rats treated with E4.

Mentions: Blood glucose level and bodyweight measurements were used to assess the systemic metabolism of the rats before and after E4 intravitreal injection. From eight to 16 weeks of age, the non-fasting and fasting BG levels in both the GK controls and the E4-treated GK group were approximately 1.9-fold to 2.4-fold and 1.3-fold to 1.6-fold higher than that in the Wistar control rats, respectively (Figure 1A,B; p<0.001 and p<0.01), while the bodyweight of the GK control and the E4-treated GK group was 3.6% to 11% lower than that of the Wistar control group, respectively (Figure 1C). The non-fasting and fasting BG levels and the bodyweight results did not differ significantly between the GK control and E4-treated group from 12 to 16 weeks of age (Figure 1, p>0.05).


Exendin-4 protects retinal cells from early diabetes in Goto-Kakizaki rats by increasing the Bcl-2/Bax and Bcl-xL/Bax ratios and reducing reactive gliosis.

Fan Y, Liu K, Wang Q, Ruan Y, Zhang Y, Ye W - Mol. Vis. (2014)

No influence on the blood glucose level or bodyweight of GK rats by E4 treatment. Non-fasting blood glucose (A), fasting blood glucose (B) and bodyweight (C) of rats with and without E4 intravitreal injection at 12 weeks of age (two-way repeated ANOVA for interaction: non-fasting blood glucose, F(16,243)=1.112, p=0.344; fasting blood glucose, F(16,243)=1.157, p=0.304; bodyweight, F(16,243)=1.336, p=0.176; n=10). Bodyweight and non-fasting and fasting blood glucose levels did not statistically differ between the GK control and E4-treated group from 12 to 16 weeks of age (two-way ANOVA followed by Bonferroni’s test: non-fasting blood glucose, p=0.43; fasting blood glucose, p=0.921; bodyweight, p=0.576; n=10). Each datum point is expressed as the means ± SEM (n=10). GK rat: Goto-Kakizaki rat; E4: Exendin-4; Control: Wistar rats treated with sham injection (normal saline); G+NS: GK rats treated with normal saline; G+E4: GK rats treated with E4.
© Copyright Policy - open-access
Related In: Results  -  Collection

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f1: No influence on the blood glucose level or bodyweight of GK rats by E4 treatment. Non-fasting blood glucose (A), fasting blood glucose (B) and bodyweight (C) of rats with and without E4 intravitreal injection at 12 weeks of age (two-way repeated ANOVA for interaction: non-fasting blood glucose, F(16,243)=1.112, p=0.344; fasting blood glucose, F(16,243)=1.157, p=0.304; bodyweight, F(16,243)=1.336, p=0.176; n=10). Bodyweight and non-fasting and fasting blood glucose levels did not statistically differ between the GK control and E4-treated group from 12 to 16 weeks of age (two-way ANOVA followed by Bonferroni’s test: non-fasting blood glucose, p=0.43; fasting blood glucose, p=0.921; bodyweight, p=0.576; n=10). Each datum point is expressed as the means ± SEM (n=10). GK rat: Goto-Kakizaki rat; E4: Exendin-4; Control: Wistar rats treated with sham injection (normal saline); G+NS: GK rats treated with normal saline; G+E4: GK rats treated with E4.
Mentions: Blood glucose level and bodyweight measurements were used to assess the systemic metabolism of the rats before and after E4 intravitreal injection. From eight to 16 weeks of age, the non-fasting and fasting BG levels in both the GK controls and the E4-treated GK group were approximately 1.9-fold to 2.4-fold and 1.3-fold to 1.6-fold higher than that in the Wistar control rats, respectively (Figure 1A,B; p<0.001 and p<0.01), while the bodyweight of the GK control and the E4-treated GK group was 3.6% to 11% lower than that of the Wistar control group, respectively (Figure 1C). The non-fasting and fasting BG levels and the bodyweight results did not differ significantly between the GK control and E4-treated group from 12 to 16 weeks of age (Figure 1, p>0.05).

Bottom Line: It also downregulated the expression of glial fibrillary acidic protein and reduced retinal reactive gliosis.Similar results were found in primary rat Müller cells under high glucose culture in vitro.E4 may protect retinal cells from diabetic attacks by activating GLP-1R, decreasing retinal cell apoptosis, and reducing retinal reactive gliosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Huashan Hospital Affiliated to Fudan University, Shanghai, China.

ABSTRACT

Purpose: Exendin-4 (E4), a long-acting agonist of the hormone glucagon-like peptide 1 receptor (GLP-1R), is administered to treat type II diabetes in the clinical setting and also shows a neuroprotective effect. Our previous studies demonstrated its protective effect in early experimental diabetic retinopathy (DR), but the molecular and cellular mechanisms are largely unknown. This study aimed to investigate the protective mechanism of a GLP-1R agonist E4 against early DR in Goto-Kakizaki (GK) rats.

Methods: Diabetic GK rats and control animals were randomly assigned to receive E4 or vehicle by intravitreal injection. The retinal function and retinal cell counts were evaluated using an electroretinogram and light microscopy. The expressions of retinal GLP-1R, mitochondria-dependent apoptosis-associated genes, reactive gliosis markers, and endoplasmic reticulum stress-related pathway genes were studied by western blotting and immunohistochemistry in vivo and in vitro.

Results: E4 significantly prevented the reduction of the b-wave and oscillatory potential amplitudes and retinal cell loss and maintained the Bcl-2/Bax and Bcl-xL/Bax ratio balances in GK rats. It also downregulated the expression of glial fibrillary acidic protein and reduced retinal reactive gliosis. Similar results were found in primary rat Müller cells under high glucose culture in vitro.

Conclusions: E4 may protect retinal cells from diabetic attacks by activating GLP-1R, decreasing retinal cell apoptosis, and reducing retinal reactive gliosis. Thus, E4 treatment may be a novel approach for early DR.

Show MeSH
Related in: MedlinePlus