The Anti-Aging Hormone Klotho Promotes Retinal Pigment Epithelium Cell Viability and Metabolism by Activating the AMPK/PGC-1α Pathway.
Shuyan ZhouJacob HumKaan TaskintunaStephanie OlayaJeremy SteinmanJunfeng MaNady GolestanehPublished in: Antioxidants (Basel, Switzerland) (2023)
Initially discovered by Makuto Kuro-o in 1997, Klotho is a putative aging-suppressor gene when overexpressed and accelerates aging when deleted in mice. Previously, we showed that α-Klotho regulates retinal pigment epithelium (RPE) functions and protects against oxidative stress. However, the mechanisms by which Klotho influences RPE and retinal homeostasis remain elusive. Here, by performing a series of in vitro and in vivo experiments, we demonstrate that Klotho regulates cell viability under oxidative stress, mitochondrial gene expression and activity by inducing the phosphorylation of AMPK and p38MAPK, which in turn phosphorylate and activate CREB and ATF2, respectively, triggering PGC-1α transcription. The inhibition of Klotho in human RPE cells using CRISPR-Cas9 gene editing confirmed that a lack of Klotho negatively affects RPE functions, including mitochondrial activity and cell viability. Proteomic analyses showed that myelin sheath and mitochondrial-related proteins are downregulated in the RPE/retina of Kl -/- compared to WT mice, further supporting our biochemical observations. We conclude that Klotho acts upstream of the AMPK/PGC-1α pathway and regulates RPE/retinal resistance to oxidative stress, mitochondrial function, and gene and protein expressions. Thus, KL decline during aging could negatively impact retinal health, inducing age-related retinal degeneration.
Keyphrases
- oxidative stress
- skeletal muscle
- induced apoptosis
- diabetic retinopathy
- optical coherence tomography
- gene expression
- crispr cas
- dna damage
- optic nerve
- ischemia reperfusion injury
- diabetic rats
- healthcare
- protein kinase
- public health
- transcription factor
- genome wide
- endothelial cells
- mental health
- copy number
- signaling pathway
- insulin resistance
- climate change
- dna methylation
- metabolic syndrome
- risk assessment
- cell proliferation
- sensitive detection
- high fat diet induced
- binding protein
- fluorescent probe
- human health
- heat shock protein