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High levels of serum prolactin protect against diabetic retinopathy by increasing ocular vasoinhibins.

Arnold E, Rivera JC, Thebault S, Moreno-Páramo D, Quiroz-Mercado H, Quintanar-Stéphano A, Binart N, Martínez de la Escalera G, Clapp C - Diabetes (2010)

Bottom Line: In rodents, hyperprolactinemia led to vasoinhibin accumulation within the retina; genetic deletion of the PRL receptor prevented this effect, indicating receptor-mediated incorporation of systemic PRL into the eye.Hyperprolactinemia reduced both VEGF-induced and diabetes-induced increase of RVP.This reduction was blocked by bromocriptine, an inhibitor of pituitary PRL secretion, which lowers the levels of circulating PRL and retinal vasoinhibins.

View Article: PubMed Central - PubMed

Affiliation: Neurobiology Institute, National University of Mexico (UNAM), Campus UNAM-Juriquilla, Juriquilla, Queretaro, Mexico.

ABSTRACT

Objective: Increased retinal vasopermeability (RVP) occurs early in diabetes and is crucial for the development of sight-threatening proliferative diabetic retinopathy (DR). The hormone prolactin (PRL) is proteolytically processed to vasoinhibins, a family of peptides that inhibit the excessive RVP related to DR. Here, we investigate the circulating levels of PRL in association with DR in men and test whether increased circulating PRL, by serving as a source of ocular vasoinhibins, can reduce the pathological RVP in diabetes.

Research design and methods: Serum PRL was evaluated in 40 nondiabetic and 181 diabetic men at various stages of DR. Retinal vasoinhibins were measured in rats rendered hyperprolactinemic by placing two anterior pituitary grafts under the kidney capsule and in PRL receptor- mice. RVP was determined in hyperprolactinemic rats subjected to the intraocular injection of vascular endothelial growth factor (VEGF) or made diabetic with streptozotocin.

Results: The circulating levels of PRL increased in diabetes and were higher in diabetic patients without retinopathy than in those with proliferative DR. In rodents, hyperprolactinemia led to vasoinhibin accumulation within the retina; genetic deletion of the PRL receptor prevented this effect, indicating receptor-mediated incorporation of systemic PRL into the eye. Hyperprolactinemia reduced both VEGF-induced and diabetes-induced increase of RVP. This reduction was blocked by bromocriptine, an inhibitor of pituitary PRL secretion, which lowers the levels of circulating PRL and retinal vasoinhibins.

Conclusions: Circulating PRL influences the progression of DR after its intraocular conversion to vasoinhibins. Inducing hyperprolactinemia may represent a novel therapy against DR.

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Related in: MedlinePlus

Hyperprolactinemia results in higher levels of retinal vasoinhibins via PRL receptor–mediated PRL internalization into the eye. A–C: Rats implanted (AP) or not (Sham) with two APs under the renal capsule for 15 days were injected (Bromo) or not with bromocriptine. A: Serum PRL levels as measured by the Nb2 cell bioassay. *P < 0.05 vs. Sham (n = 20 rats per group). Western blot analysis of vasoinhibin levels in the retina (B) and corresponding densitometric analysis normalized to β-tubulin (C). *P < 0.05 vs. Sham (n = 3, each a pool of four retinas). D: Representative immunohistochemistry of rat ciliary body sections stained with monoclonal anti-PRL receptor (PRLR) antibody or without primary antibody (left) (n = 3 independent experiments). Scale bar, 50 μm. E: Serum PRL levels assessed with the Nb2 cell bioassay in wild-type (wt) and PRLR- (PRL−/−) mice. *P < 0.05 vs. wild-type mice (n = 8 mice per group). Representative Western blot analysis of retinal vasoinhibins in wild-type and PRLR−/− mice (different lanes from the same gel) (F) and corresponding evaluation of retinal vasoinhibins by densitometry normalized to β-tubulin (G) (n = 3, each a pool of six retinas). Data in A, C, E, and G are means ± SEM. Vi, vasoinhibins.
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Figure 2: Hyperprolactinemia results in higher levels of retinal vasoinhibins via PRL receptor–mediated PRL internalization into the eye. A–C: Rats implanted (AP) or not (Sham) with two APs under the renal capsule for 15 days were injected (Bromo) or not with bromocriptine. A: Serum PRL levels as measured by the Nb2 cell bioassay. *P < 0.05 vs. Sham (n = 20 rats per group). Western blot analysis of vasoinhibin levels in the retina (B) and corresponding densitometric analysis normalized to β-tubulin (C). *P < 0.05 vs. Sham (n = 3, each a pool of four retinas). D: Representative immunohistochemistry of rat ciliary body sections stained with monoclonal anti-PRL receptor (PRLR) antibody or without primary antibody (left) (n = 3 independent experiments). Scale bar, 50 μm. E: Serum PRL levels assessed with the Nb2 cell bioassay in wild-type (wt) and PRLR- (PRL−/−) mice. *P < 0.05 vs. wild-type mice (n = 8 mice per group). Representative Western blot analysis of retinal vasoinhibins in wild-type and PRLR−/− mice (different lanes from the same gel) (F) and corresponding evaluation of retinal vasoinhibins by densitometry normalized to β-tubulin (G) (n = 3, each a pool of six retinas). Data in A, C, E, and G are means ± SEM. Vi, vasoinhibins.

Mentions: Serum PRL is incorporated into the eye and converted to vasoinhibins. To investigate whether serum PRL could serve as a source of retinal vasoinhibins we used a rat model of hyperprolactinemia induced by placing two AP grafts under the kidney capsule for 15 days (9). As demonstrated by the Nb2 cell bioassay and Western blot, AP-grafted rats showed a sixfold increase of serum PRL (Fig. 2A, n = 20) and threefold higher levels of vasoinhibins in the retina (Fig. 2B and C, n = 3) compared with the nongrafted controls. Injection of grafted rats with the dopamine D2 receptor agonist bromocriptine, an inhibitor of PRL secretion (12), reduced both PRL in the circulation and vasoinhibins in the retina to basal levels (Fig. 2A–C).


High levels of serum prolactin protect against diabetic retinopathy by increasing ocular vasoinhibins.

Arnold E, Rivera JC, Thebault S, Moreno-Páramo D, Quiroz-Mercado H, Quintanar-Stéphano A, Binart N, Martínez de la Escalera G, Clapp C - Diabetes (2010)

Hyperprolactinemia results in higher levels of retinal vasoinhibins via PRL receptor–mediated PRL internalization into the eye. A–C: Rats implanted (AP) or not (Sham) with two APs under the renal capsule for 15 days were injected (Bromo) or not with bromocriptine. A: Serum PRL levels as measured by the Nb2 cell bioassay. *P < 0.05 vs. Sham (n = 20 rats per group). Western blot analysis of vasoinhibin levels in the retina (B) and corresponding densitometric analysis normalized to β-tubulin (C). *P < 0.05 vs. Sham (n = 3, each a pool of four retinas). D: Representative immunohistochemistry of rat ciliary body sections stained with monoclonal anti-PRL receptor (PRLR) antibody or without primary antibody (left) (n = 3 independent experiments). Scale bar, 50 μm. E: Serum PRL levels assessed with the Nb2 cell bioassay in wild-type (wt) and PRLR- (PRL−/−) mice. *P < 0.05 vs. wild-type mice (n = 8 mice per group). Representative Western blot analysis of retinal vasoinhibins in wild-type and PRLR−/− mice (different lanes from the same gel) (F) and corresponding evaluation of retinal vasoinhibins by densitometry normalized to β-tubulin (G) (n = 3, each a pool of six retinas). Data in A, C, E, and G are means ± SEM. Vi, vasoinhibins.
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Figure 2: Hyperprolactinemia results in higher levels of retinal vasoinhibins via PRL receptor–mediated PRL internalization into the eye. A–C: Rats implanted (AP) or not (Sham) with two APs under the renal capsule for 15 days were injected (Bromo) or not with bromocriptine. A: Serum PRL levels as measured by the Nb2 cell bioassay. *P < 0.05 vs. Sham (n = 20 rats per group). Western blot analysis of vasoinhibin levels in the retina (B) and corresponding densitometric analysis normalized to β-tubulin (C). *P < 0.05 vs. Sham (n = 3, each a pool of four retinas). D: Representative immunohistochemistry of rat ciliary body sections stained with monoclonal anti-PRL receptor (PRLR) antibody or without primary antibody (left) (n = 3 independent experiments). Scale bar, 50 μm. E: Serum PRL levels assessed with the Nb2 cell bioassay in wild-type (wt) and PRLR- (PRL−/−) mice. *P < 0.05 vs. wild-type mice (n = 8 mice per group). Representative Western blot analysis of retinal vasoinhibins in wild-type and PRLR−/− mice (different lanes from the same gel) (F) and corresponding evaluation of retinal vasoinhibins by densitometry normalized to β-tubulin (G) (n = 3, each a pool of six retinas). Data in A, C, E, and G are means ± SEM. Vi, vasoinhibins.
Mentions: Serum PRL is incorporated into the eye and converted to vasoinhibins. To investigate whether serum PRL could serve as a source of retinal vasoinhibins we used a rat model of hyperprolactinemia induced by placing two AP grafts under the kidney capsule for 15 days (9). As demonstrated by the Nb2 cell bioassay and Western blot, AP-grafted rats showed a sixfold increase of serum PRL (Fig. 2A, n = 20) and threefold higher levels of vasoinhibins in the retina (Fig. 2B and C, n = 3) compared with the nongrafted controls. Injection of grafted rats with the dopamine D2 receptor agonist bromocriptine, an inhibitor of PRL secretion (12), reduced both PRL in the circulation and vasoinhibins in the retina to basal levels (Fig. 2A–C).

Bottom Line: In rodents, hyperprolactinemia led to vasoinhibin accumulation within the retina; genetic deletion of the PRL receptor prevented this effect, indicating receptor-mediated incorporation of systemic PRL into the eye.Hyperprolactinemia reduced both VEGF-induced and diabetes-induced increase of RVP.This reduction was blocked by bromocriptine, an inhibitor of pituitary PRL secretion, which lowers the levels of circulating PRL and retinal vasoinhibins.

View Article: PubMed Central - PubMed

Affiliation: Neurobiology Institute, National University of Mexico (UNAM), Campus UNAM-Juriquilla, Juriquilla, Queretaro, Mexico.

ABSTRACT

Objective: Increased retinal vasopermeability (RVP) occurs early in diabetes and is crucial for the development of sight-threatening proliferative diabetic retinopathy (DR). The hormone prolactin (PRL) is proteolytically processed to vasoinhibins, a family of peptides that inhibit the excessive RVP related to DR. Here, we investigate the circulating levels of PRL in association with DR in men and test whether increased circulating PRL, by serving as a source of ocular vasoinhibins, can reduce the pathological RVP in diabetes.

Research design and methods: Serum PRL was evaluated in 40 nondiabetic and 181 diabetic men at various stages of DR. Retinal vasoinhibins were measured in rats rendered hyperprolactinemic by placing two anterior pituitary grafts under the kidney capsule and in PRL receptor- mice. RVP was determined in hyperprolactinemic rats subjected to the intraocular injection of vascular endothelial growth factor (VEGF) or made diabetic with streptozotocin.

Results: The circulating levels of PRL increased in diabetes and were higher in diabetic patients without retinopathy than in those with proliferative DR. In rodents, hyperprolactinemia led to vasoinhibin accumulation within the retina; genetic deletion of the PRL receptor prevented this effect, indicating receptor-mediated incorporation of systemic PRL into the eye. Hyperprolactinemia reduced both VEGF-induced and diabetes-induced increase of RVP. This reduction was blocked by bromocriptine, an inhibitor of pituitary PRL secretion, which lowers the levels of circulating PRL and retinal vasoinhibins.

Conclusions: Circulating PRL influences the progression of DR after its intraocular conversion to vasoinhibins. Inducing hyperprolactinemia may represent a novel therapy against DR.

Show MeSH
Related in: MedlinePlus