<i>Pgc-1α</i> repression and high-fat diet induce age-related macular degeneration-like phenotypes in mice

Zhang, Meng; Chu, Yi; Mowery, Joseph; Konkel, Brandon; Galli, Susana; Theos, Alexander C.; Golestaneh, Nady

doi:10.1242/dmm.032698

Cited by 47 publications

(41 citation statements)

References 52 publications

(68 reference statements)

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“…These results therefore suggest that PGC-1α may be protective in microvascular diseases, including retinopathies. In line with these results, PGC-1α heterozygous mice exposed to a high fat diet developed age-related macular degeneration-like abnormalities in the retinal pigmented epithelium and local inflammatory responses [83]. In the context of kidney diseases, endothelial dysfunction associated with hypertension, obesity and/or diabetes is a key mechanism in CKD progression and CKD-related cardiovascular complications [84][85][86][87].…”

Section: Endotheliumsupporting

confidence: 53%

The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

et al. 2020

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Chronic kidney disease (CKD) is one of the fastest growing causes of death worldwide, emphasizing the need to develop novel therapeutic approaches. CKD predisposes to acute kidney injury (AKI) and AKI favors CKD progression. Mitochondrial derangements are common features of both AKI and CKD and mitochondria-targeting therapies are under study as nephroprotective agents. PGC-1α is a master regulator of mitochondrial biogenesis and an attractive therapeutic target. Low PGC-1α levels and decreased transcription of its gene targets have been observed in both preclinical AKI (nephrotoxic, endotoxemia, and ischemia-reperfusion) and in experimental and human CKD, most notably diabetic nephropathy. In mice, PGC-1α deficiency was associated with subclinical CKD and predisposition to AKI while PGC-1α overexpression in tubular cells protected from AKI of diverse causes. Several therapeutic strategies may increase kidney PGC-1α activity and have been successfully tested in animal models. These include AMP-activated protein kinase (AMPK) activators, phosphodiesterase (PDE) inhibitors, and anti-TWEAK antibodies. In conclusion, low PGC-1α activity appears to be a common feature of AKI and CKD and recent characterization of nephroprotective approaches that increase PGC-1α activity may pave the way for nephroprotective strategies potentially effective in both AKI and CKD.

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Section: Endotheliumsupporting

confidence: 53%

The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

et al. 2020

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“…Mechanistic insights into mitochondrial dysfunction in AMD have highlighted a protective role for proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in RPE during AMD [94,108]. Repression of PGC-1α in mice and exposure to a high-fat diet resulted in AMD-like abnormalities in the RPE [109]. Work in our laboratory identified PGC-1α as a master regulator of mitochondrial biogenesis and function in RPE, increasing in expression with RPE maturation [110].…”

Section: Metabolic Dysfunction and Autophagy In Amdmentioning

confidence: 97%

EMT and EndMT: Emerging Roles in Age-Related Macular Degeneration

Shu

Butcher

Saint‐Geniez

2020

IJMS

174

138

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Epithelial–mesenchymal transition (EMT) and endothelial–mesenchymal transition (EndMT) are physiological processes required for normal embryogenesis. However, these processes can be hijacked in pathological conditions to facilitate tissue fibrosis and cancer metastasis. In the eye, EMT and EndMT play key roles in the pathogenesis of subretinal fibrosis, the end-stage of age-related macular degeneration (AMD) that leads to profound and permanent vision loss. Predominant in subretinal fibrotic lesions are matrix-producing mesenchymal cells believed to originate from the retinal pigment epithelium (RPE) and/or choroidal endothelial cells (CECs) through EMT and EndMT, respectively. Recent evidence suggests that EMT of RPE may also be implicated during the early stages of AMD. Transforming growth factor-beta (TGFβ) is a key cytokine orchestrating both EMT and EndMT. Investigations in the molecular mechanisms underpinning EMT and EndMT in AMD have implicated a myriad of contributing factors including signaling pathways, extracellular matrix remodelling, oxidative stress, inflammation, autophagy, metabolism and mitochondrial dysfunction. Questions arise as to differences in the mesenchymal cells derived from these two processes and their distinct mechanistic contributions to the pathogenesis of AMD. Detailed discussion on the AMD microenvironment highlights the synergistic interactions between RPE and CECs that may augment the EMT and EndMT processes in vivo. Understanding the differential regulatory networks of EMT and EndMT and their contributions to both the dry and wet forms of AMD can aid the development of therapeutic strategies targeting both RPE and CECs to potentially reverse the aberrant cellular transdifferentiation processes, regenerate the retina and thus restore vision.

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“…However, it is justified to state that PGC-1α impairment in the retina may result in AMD or AMD-like state. Moreover, it can be speculated that autophagy and mitochondrial quality control can be involved, and this speculation has been recently supported by experiments of Zhang et al [114]. These authors showed that mice with the deletion of one copy of the PGC-1α gene and fed with a fat-rich diet showed AMD-like phenotype in RPE, including diminished mitochondrial activity and autophagic flux.…”

Section: Discussionmentioning

confidence: 89%

PGC-1α Protects RPE Cells of the Aging Retina against Oxidative Stress-Induced Degeneration through the Regulation of Senescence and Mitochondrial Quality Control. The Significance for AMD Pathogenesis

Kaarniranta

Kajdanek

Morawiec

et al. 2018

IJMS

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PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) is a transcriptional coactivator of many genes involved in energy management and mitochondrial biogenesis. PGC-1α expression is associated with cellular senescence, organismal aging, and many age-related diseases, including AMD (age-related macular degeneration), an important global issue concerning vision loss. We and others have developed a model of AMD pathogenesis, in which stress-induced senescence of retinal pigment epithelium (RPE) cells leads to AMD-related pathological changes. PGC-1α can decrease oxidative stress, a key factor of AMD pathogenesis related to senescence, through upregulation of antioxidant enzymes and DNA damage response. PGC-1α is an important regulator of VEGF (vascular endothelial growth factor), which is targeted in the therapy of wet AMD, the most devastating form of AMD. Dysfunction of mitochondria induces cellular senescence associated with AMD pathogenesis. PGC-1α can improve mitochondrial biogenesis and negatively regulate senescence, although this function of PGC-1α in AMD needs further studies. Post-translational modifications of PGC-1α by AMPK (AMP kinase) and SIRT1 (sirtuin 1) are crucial for its activation and important in AMD pathogenesis.

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Pgc-1α repression and high-fat diet induce age-related macular degeneration-like phenotypes in mice

Cited by 47 publications

References 52 publications

The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

EMT and EndMT: Emerging Roles in Age-Related Macular Degeneration

PGC-1α Protects RPE Cells of the Aging Retina against Oxidative Stress-Induced Degeneration through the Regulation of Senescence and Mitochondrial Quality Control. The Significance for AMD Pathogenesis

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