Peroxisome proliferator-activated receptor alpha (PPARα) and its role in diabetic retinopathy: Novel insights

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5 January 2015

Both the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Diabetes-Eye (ACCORD-Eye) studies provided consistent evidence of beneficial effects with fenofibrate in slowing the progression of early stage diabetic retinopathy (DR). However, questions remain regarding the underlying mode of action of fenofibrate, given that there was no relationship between the lipid-modifying effects of fenofibrate and the progression of DR. This mechanistic study indicates a key role for peroxisome proliferator-activated receptor alpha (PPARα) in the human and rodent retina, reinforcing its potential as a therapeutic target.

Hu Y, Chen Y, Ding L, He X, Takahashi Y, Gao Y, Shen W, Cheng R, Chen Q, Qi X, Boulton ME, Ma JX. Pathogenic role of diabetes-induced PPAR-? down-regulation in microvascular dysfunction. Proc Natl Acad Sci U S A 2013;110:15401-6.

STUDY SUMMARY

Objective:

To investigate the effects of expression of PPARa in the retina

Study design:

Mechanistic studies using both in vitro cell culture models and animal models of diabetes

Experimental models:

• In vitro model; multiple cell types in the retina from both humans and rats
• Experimental models of diabetes; streptozocin-induced diabetic rats; a genetic model of type 1 diabetes (Akita mice); and a model of type 2 diabetes (db/db mice)
• Experimental model: PPARα deficient mice with and without diabetes

Primary variable:

- In vitro model: expression of PPARa in different cell types and impact of high glucose levels on its expression

- Experimental models of diabetes: assessment of the effect of down-regulation of PPARa, PPARb and PPARg expression, and high glucose levels on retinal vascular function

- PPARa deficient mice: assessment of retinal vessel function (impact on number of pericytes, vascular permeability and inflammation)

Methods:

Established immunostaining techniques were used for assessment of PPARa expression in cell culture models. The direct effects of PPARα on endothelial cell migration and proliferation were investigated using an in vitro scratch-wound healing assay.

Western blot analysis was used to determine protein levels of PPARα, PPARb and PPARg in the retina; real-time RT-PCR was used to measure mRNA levels of PPARa, PPARb and PPARg in the retina. To determine the severity of the diabetes-induced retinal vascular leakage, a retinal vascular permeability assay was used. Retinal inflammation in PPARα deficient and wild type (control) mice under normal/diabetic conditions was assessed using a retinal leukostasis assay.

Main results:

- In vitro studies showed that PPARα is expressed in multiple cell types in the retina, notably in glial cells, including Müller cells, and in the inner retina.

- In experimental models of diabetes (both type 1 and type 2), expression of PPARα (but not PPARb and PPARg) is selectively down-regulated in the retina. High glucose levels also down-regulate PPARα expression in retinal cell culture studies; however, there was no effect on PPARb and PPARg expression.

- PPARα deficient mice with diabetes developed more severe vascular impairment and retinal inflammation compared with wild type (control) mice with diabetes.

- PPARα overexpression in the retina alleviated vascular leakage and retinal inflammation in diabetic rats. In an in vitro model, PPARα overexpression inhibited migration and proliferation of human retinal capillary endothelial cells.

Authors’ conclusion:

These findings revealed that diabetes-induced down-regulation of PPARα plays an important role in DR. Up-regulation or activation of PPARα may represent a novel therapeutic strategy for DR.

COMMENT

Findings from this study highlight an important direct role for PPARα in diabetic retinopathy. Expression of PPARα was downregulated in both type 1 and type 2 diabetes models, and in mice deficient in PPARα, there was exacerbation of diabetes-induced retinal vascular leakage and retinal inflammation. In contrast, over-expression of PPARα in the retina of diabetic rats significantly alleviated diabetic retinopathy. Taken together with evidence of other potential mechanisms that may explain a beneficial effect of PPARα in the retina, including inhibition of vascular cell adhesion molecules on the endothelium, useful in preventing leukostasis, critical to the pathogenesis of proliferative DR,(1) as well as reduction in inflammation and modulation of the Wnt signalling pathway,(2,3) these findings suggest that retinal PPARα represents a novel therapeutic target.

Indeed, these mechanistic insights help to explain the results of both the FIELD and ACCORD-Eye studies.(4,5) Considering both studies together, there was a relative reduction in DR progression of 30-40% over 4-5 years, with greater benefit observed in patients with pre-existing DR. These data underlie recent recommendations by the Residual Risk Reduction Initiative for a role for PPARa agonism in reducing the residual risk of DR that persists in patients with type 2 diabetes despite best standards of care.(6) Whether more potent and selective agonists of PPARa, such as the selective peroxisome proliferator-activated receptor alpha modulator (SPPARM) K-877, may offer greater benefit certainly merits investigation.

References

1. Israelian-Konaraki Z, Reaven PD. Peroxisome proliferator-activated receptor-alpha and atherosclerosis: from basic mechanisms to clinical implications. Cardiol Rev 2005;13:240–246.

2. Chen Y, Hu Y, Zhou T et al. Activation of the Wnt pathway plays a pathogenic role in diabetic retinopathy in humans and animal models. Am J Pathol 2009;175: 2676-2685.

3. Krysiak R, Labuzek K, Okopien B. Effect of atorvastatin and fenofibric acid on adipokine release from visceral and subcutaneous adipose tissue of patients with mixed dyslipidemia and normolipidemic subjects. Pharmacol Rep 2009;61:1134-1145.

4. Keech AC; Mitchell P; Summanen PA et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007;370:1687-1697.

5. ACCORD Study Group; ACCORD Eye Study Group, Chew EY, Ambrosius WT, Davis MD et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010;363:233-244.

6. Hermans MP, Fruchart JC, Davignon J et al. Residual Microvascular Risk in type 2 diabetes: is it time for a re-think? A perspective from the Residual Risk Reduction Initiative. Available at: http://omicsonline.org/open-access/residual-microvascular-risk-in-type-diabetes-in-is-it-time-for-a-re-think-a-perspective-from-the-residual-risk-reduction-initiative.

Key words

diabetic retinopathy; peroxisome proliferator-activated receptor alpha; experimental models; microvascular effects; fenofibrate