Retinal homeostasis and metformin-induced protection are not affected by retina-specific Pparδ knockout

Abstract

Peroxisome proliferator-activated receptors (PPARs) are a family of three nuclear hormone receptors (PPARα, PPARδ, and PPARγ) that are known to regulate expression of lipid metabolism and oxidative stress genes. Given their role in reducing oxidative stress in a variety of tissues, these genes are likely important for retinal homeostasis. This hypothesis has been further supported by recent studies suggesting that PPAR-activating drugs are protective against retinal degenerations. The objective of the present study was to determine the role of PPARδ in the neuroretina. RNA-seq data show that Pparα and Pparδ are both expressed in the retina, but that Pparδ is expressed at 4-fold higher levels. Single-cell RNAseq data show that Pparδ is broadly expressed in all retinal cell types. To determine the importance of Pparδ to the retina, we generated retina-specific Ppar δ knockout mice. We found that deletion of Pparδ had a minimal effect on retinal function or morphology out to 12 months of age and did not increase retinal sensitivity to oxidative stress induced by exposure to bright light. While data show that PPARδ levels were increased by the drug metformin, PPARδ was not necessary for metformin-induced protection from light damage. These data suggest that Ppar δ either has a redundant function with Pparα or is not essential for normal neuroretina function or resistance to oxidative stress.

Metformin inhibits methylglyoxal-induced retinal pigment epithelial cell death and retinopathy via AMPK-dependent mechanisms: Reversing mitochondrial dysfunction and upregulating glyoxalase 1

“…Several studies have demonstrated the underlying mechanisms for the protective action of metformin in various cell types. The protection is associated with decreased oxidative stress [ 28 , 29 ], increased mitochondrial energy production [ 30 ] and autophagy [ 26 ], as well as reduced VEGF-A expression [ 24 , 31 ]. Nevertheless, metformin may also directly suppress respiratory complex I, leading to deteriorate mitochondrial dysfunction and in turn activate AMP-activated protein kinase (AMPK) [ 32 ].…”

NFkB‐signaling promotes glial reactivity and suppresses Müller glia‐mediated neuron regeneration in the mammalian retina

“…to act at PI3K/Akt upstream of NFkB (Giri et al, 2004) and act at PPAR-gamma in an astrocyte cell line (Forman et al, 1995). However, it has been shown that PPAR-gamma is not expressed in mouse retina (Xu et al, 2020), and we did not detect PPAR-gamma in the scRNAseq libraries (not shown). We observed a significant decrease in numbers of GFP + /Sox2 + MG in damaged retinas treated with PGJ2 compared to controls (Figure 2c,d).…”

Metformin and retinal diseases in preclinical and clinical studies: Insights and review of literature

“…AKT, ERK); 34 inhibition of O-GlcNAc modification and activation of cytotoxic molecules; 35 and activation of nuclear hormone receptors including PPARΔ. 39 An important consideration moving forward is to identify exactly where along the course of a particular retinal disease metformin is able to exert its maximal effect. Many of the preclinical studies showing a benefit from metformin use involved either pretreatment of animals or cell lines with metformin prior to induction with a pathologic stressor or shortly thereafter.…”

“…Furthermore, PPARΔ may either be nonessential or share redundant functions with other mediators of the oxidative stress response of the retina. 39…”