Fenofibrate benefits in diabetic retinopathy mediated through PPARα

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By Eleanor McDermid, Senior medwireNews Reporter

Peroxisome proliferator–activated receptor (PPAR)α exerts protective effects on retinal pericytes, shows research that explains why fenofibrate is protective against diabetic retinopathy.

Two major clinical trials of fenofibrate in patients with Type 2 diabetes have shown that the drug offers “robust” protection against microvascular complications, including diabetic retinopathy, say study author Jian-xing Ma (University of Oklahoma Health Sciences Center, Oklahoma City, USA) and colleagues.

Fenofibrate is a PPARα agonist, but it has been suggested that the drug may have PPARα-independent effects. However, the team’s findings indicate that “[a]ll of the beneficial effects of fenofibrate can be achieved by overexpression of PPARα.”

Using diabetic mice, the researchers showed that fenofibrate treatment protects retinal pericytes; it reduced the number of retinal acellular capillaries and pericyte ghosts seen without treatment and attenuated the reduction in pericyte density.

In cultured human retinal capillary pericytes, fenofibrate reduced apoptotic cell death induced by oxidative stress. It achieved this by preventing increased levels of reactive oxygen species via suppression of the NF-κB/NOX4 pathway.

Of note, the team replicated all these protective effects by overexpressing PPARα in the cultured pericytes, indicating that the beneficial effects of fenofibrate occurred because of its ability to upregulate PPARα. Conversely, pericytes entirely lacking the gene encoding PPARα had increased susceptibility to cell death caused by oxidative stress.

Noting that reactive oxygen species in cells under oxidative stress may be partly due to decreased mitochondrial respiration, Ma et al also observed that mitochondrial oxygen consumption decreased by about 50% when the pericytes were under oxidative stress. This reduction was reversed by treatment with fenofibrate or a PPARα-containing adenovirus.

In diabetic mice, those lacking the PPARα gene had significantly lower retinal pericyte density than wild-type diabetic mice at 6 months after diabetes onset, “indicating that PPARα is an endogenous protective factor in pericytes under a diabetic milieu.”

Fenofibrate was able to attenuate the pericyte loss in wild-type mice but not in those lacking PPARα.

“Our results from both PPARα overexpression and PPARα knockout mice and primary cells suggest that the beneficial effects of fenofibrate on [diabetic retinopathy] are through a PPARα-dependent mechanism”, the researchers conclude in The American Journal of Pathology. “These findings reveal a novel function of PPARα in the retina.”

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