# Role of Peoxisome Proliferator Activator Receptorγ on Blood Retinal Barrier Breakdown

Authors: Yasuo Yanagi
Journal: PPAR Research
 (2008)

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## Abstract

The retinal vessels have two barriers: the retinal pigment epithelium and the retinal vascular endothelium. Each barrier exhibits increased permeability under various pathological conditions. This condition is referred to as blood retinal barrier (BRB) breakdown. Clinically, the most frequently encountered condition causing BRB breakdown is diabetic retinopathy. In recent studies, inflammation has been linked to BRB breakdown and vascular leakage in diabetic retinopathy. Biological support for the role of inflammation in early diabetes is the adhesion of leukocytes to the retinal vasculature (leukostasis) observed in diabetic retinopathy.PPAR
γ is a member of a ligand-activated nuclear receptor superfamily and plays a critical role in a variety of biological processes, including adipogenesis, glucose metabolism, angiogenesis, and inflammation. There is now strong experimental evidence to support the theory that PPAR
γ inhibits diabetes-induced retinal leukostasis and leakage, playing an important role in the pathogenesis of diabetic retinopathy. Therapeutic targeting of PPAR
γ may be beneficial to diabetic retinopathy.


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## Body

## 1. Blood Retinal Barrier (BRB) Breakdown in Diabetic Retinopathy

The  retinal vessels have a
barrier consisting of the tight junction of the retinal pigment epithelium and
the retinal vascular endothelium. Each
barrier exhibits increased permeability under various pathological
conditions. This condition is referred
to as blood retinal barrier (BRB) breakdown.
Clinically, the most frequently encountered condition that induces
vascular permeability is diabetic retinopathy [1]. BRB breakdown causes retinal edema. Clinically, the retinal edema often affects
macula, the highly sensitive area of the central retina, and often severely affects
vision (Figure 1). The frequency of
diabetic macular edema ranges from 2% to 13.3% of all diabetic patients, and
6.7% to 62% of insulin-dependent diabetic patients, and its incidence is 1.3%
to 5.1% over a four-year observation period [2]. Due to the enhanced retinal vascular permeability,
endothelial cell damage and capillary nonperfusion are aggravated. Much effort has been directed toward
establishing effective treatments, and recent clinical studies have found that laser
photocoagulation, pars plana vitrectomy, and antivascular endothelial growth
factor (VEGF) therapy might be effective in ameliorating macular edema [3–6], but the
treatment efficacy is limited and the results of the preliminary clinical
investigation will have to be confirmed by further studies.Macular edema in diabetic
retinopathy. (a) Macular edema
in diabetic retinopathy. (b) Increased
vascular permeability is observed by fluorescin angiography. Note the leakage of the fluorescent dye
showing the blood retinal barrier breakdown.
Although the retinopathy is mild, this patient has a visual acuity of
20/200 due to severe macular edema.
(a)
(b)


## 2. The Role of Inflammation in BRB Breakdown

In recent
studies, inflammation has been linked to vascular leakage in diabetic
retinopathy [7]. Biological support for
the role of inflammation in early diabetes is the adhesion of leukocytes to the
retinal vasculature (leukostasis) observed in both experimental diabetic
retinopathy in rats and in human diabetic retinopathy [8, 9]. Increased adhesion of leukocytes to the
retinal vasculature is considered to promote vascular leakage. Thus, leukostasis is considered to be a
critical event in the pathogenesis of diabetic retinopathy. Clinical investigations have demonstrated
that the vitreous level of VEGF protein is higher in patients with diabetic
macular edema than in patients with other conditions [10]. Ample evidence suggests that the adhesion of
leukocytes to the retinal capillaries is controlled by vascular endothelial
growth factor (VEGF), and focal adhesion molecules such as the intercellular
adhesion molecule 1 (ICAM1) [11]. It is
a commonly accepted molecular mechanism of leukocyte adhesion that VEGF
drives the upregulation of the ICAM-1 molecule in the retinal endothelial cells
[12, 13], and that this upregulated ICAM-1, together with upregulated leukocyte
integrin CD18, triggers adhesion of leukocytes to the retinal vessels
[14]. Indeed, CD18(−/−) and
ICAM-1 (−/−) mice demonstrate significantly fewer adherent leukocytes in the
retinal vasculature after the induction of diabetes with streptozotocin (STZ)
[15]. It is, however, not
only VEGF but also several other molecules that are involved in the expression
of ICAM-1. NF-κB molecules, activated by inflammation,
also drive ICAM-1 expression [16]. Furthermore, blockage
of the bioactivity of VEGF or ICAM-1 or inhibition of inflammatory pathways leads to decreased retinal leukocyte
adhesion and reduced vascular leakage [17].
Thus, it is generally assumed that the upregulation of the adhesion molecule,
triggered by VEGF and other inflammatory stimuli, is important in the
leukostasis (Figure 2).Figure 2
Schematic representation
of the molecular mechanism of macular edema. VEGF drives the expression of
ICAM-1 in the retinal vessels, which subsequently makes CD18+ leukocytes
adherent to the retinal vessels.
Adhesion of leukocytes to the retinal vessels leads to increased
vascular leakage, subsequent endothelial cell damage, and capillary
nonperfusion.


## 3. PPARγ and Inflammation

PPARγ is a member of a ligand-activated
nuclear receptor superfamily and plays a critical role in a variety of
biological processes, including adipogenesis, glucose metabolism, angiogenesis,
and inflammation [18]. Synthetic ligands
of PPARγ, that is, thiazolidine derivatives such as rosiglitazone and
pioglitazone, are used as oral antihyperglycemic agents for the therapy of non-insulin-dependent
diabetes mellitus. In addition, recent
studies have shown that PPARγ ligands
modulate the production of inflammatory mediators [19]. Actually, it has been reported that
PPARγ ligands, such as rosiglitazone and
pioglitazone, suppress inflammatory diseases such as adjuvant-induced arthritis
[19]. Importantly,
some evidence suggests that PPARγ
is involved in the regulation of adhesion molecules. Previously, it has been demonstrated that PPARγ ligand suppressed ICAM-1 expression in a
murine model of intestinal ischemia-reperfusion injury [20] and in human umbilical vein endothelial
cells in vitro [21]. Some of these
anti-inflammatory functions are mediated through the inhibition of NF-κB activation (Figure 3). Considering the close link between
inflammation and diabetes, it is rational to consider that PPARγ
ligand therapy may also improve diabetic retinopathy.Figure 3
PPARγ exerts anti-inflammatory effects. Schematic representation showing molecular pathways mediating the anti-inflammatory effects of PPARγ
ligands


## 4. PPARγ in BRB Breakdown

We investigated
the effects of a synthetic PPARγ ligand, rosiglitazone, on an
experimental diabetic model [22].
Additionally, heterozygous PPARγ-deficient (+/-) mice were used in an
experimental model to determine whether endogenous PPARγ
played a role [22]. Experimental
diabetes was induced by intraperitoneal injection of STZ. This model is considered to destroy
pancreatic beta cells completely [22]
Retinal leukostasis quantification was performed by counting the number
of adherent leukocytes after fluorescein-isothiocyanide (FITC)- Concanavalin A
lectin (Con A) perfusion. A retinal
leakage assay was performed by evaluating the retinal concentration of
FITC-dextran after the animals were perfused.
The results showed the PPARγ agonist, rosiglitazone, inhibited both the
retinal leukostasis and retinal leakage observed in the experimental diabetic
rats and that the decreased expression of the endogenous PPARγ in mice leads to the aggravation of
retinal leukostasis and retinal leakage in diabetic mice. Together, these findings support the theory
that the PPARγ
signaling pathway inhibits diabetes-induced retinal leukostasis and leakage. In addition, it was demonstrated that PPARγ ligand suppresses ICAM-1 expression, but
not VEGF expression, raising the possibility that NF-κB mediated ICAM-1 is suppressed by PPARγ ligand (Figure 4).Figure 4
Involvement of PPARγ
ligand and its receptor system in retinal leukostasis and vacular permeability. Schematic representation showing
the role of PPARγ system in the retinal leukostasis and
vascular permeability in diabetic retinopathyThese results
provide strong evidence to support the theory that PPARγ
activity plays an important role in the pathogenesis of diabetic retinopathy and
introduce the novel possibility that the therapeutic targeting of PPARγ may
be beneficial to diabetic retinopathy.



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*Source: 679237-2008-01-27.xml*