C1q/TNF-related Protein 9 Inhibits High Glucose–Induced Oxidative Stress and Apoptosis in Retinal Pigment Epithelial Cells Through the Activation of AMPK/Nrf2 Signaling Pathway

Abstract

Diabetic retinopathy (DR) is one of the common complications of diabetes mellitus. C1q/TNF-related protein 9 (CTRP9) has been demonstrated to be associated with the progression of diabetes and relative complications. However, its role in DR and underlying action of mechanism are not yet well understood. In the present study, human retinal pigment epithelial ARPE-19 cells were cultured under high concentration of glucose to simulate hyperglycemia condition in vitro. Our results showed that the expression of CTRP9 was significantly decreased in high glucose (HG)–stimulated ARPE-19 cells. CTRP9 overexpression improved HG-caused reduction in cell viability of ARPE-19 cells. CTRP9 overexpression significantly attenuated HG-induced oxidative stress, as proved by decreased levels of reactive oxygen species and malondialdehyde, and increased superoxide dismutase activity. Moreover, CTRP9 also prevented apoptosis in ARPE-19 cells in response to HG stimulation with decreased caspse-3 activity and bax expression, as well as increased bcl-2 expression. In contrast, knockdown of CTRP9 aggravated HG-induced oxidative stress and apoptosis. Furthermore, CTRP9 significantly induced the activation of AMPK/Nrf2 pathway in HG-induced ARPE-19 cells. Notably, inhibiting AMPK or Nrf2 blocked the protective effect of CTRP9 on ARPE-19 cells exposed to HG stimulation. Taken together, our findings suggested a protective effect of CTRP9 on HG-induced ARPE-19 cells and a putative mechanism involving the activation of AMPK/Nrf2 signaling pathway.

C1q/TNF-Related Protein 9 Attenuates Atherosclerosis by Inhibiting Hyperglycemia-Induced Endothelial Cell Senescence Through the AMPKα/KLF4 Signaling Pathway

“…AMPK, a serine/threonine kinase sensitive to cellular energy alterations and processes linking energetics to longevity, acts as a major downstream component of CTRP9 signaling. CTRP9 overexpression has been reported to protect against HGinduced endothelial oxidative damage and apoptosis by phosphorylating AMPK (Cheng et al, 2016;Cheng et al, 2020). Treatment with recombinant CTRP9 protein significantly increased the phosphorylation of AMPK and inhibited cytokine-induced vascular inflammation and leukocyte adhesiveness in human aortic endothelial cells (Jung et al, 2016).…”

Stimulation of AMPK Prevents Diabetes‐Induced Photoreceptor Cell Degeneration

“…AGEs can destroy the biological function of mitochondria [19] and inhibit normal autophagy in cells [20], which provides an important platform for researchers to study the molecular mechanisms and drug interventions associated with mitochondrial and autophagy-related central nervous system diseases. Some studies reported that AMPK showed protective effects on different cell lines, such as podocytes [21], hippocampal neurons [22], retinal pigment epithelium ARPE-19 cells [23], and Müller cells [24]. According to some reports, AMPK directly promotes autophagy by phosphorylating autophagy-related proteins in the mTORC1, ULK1, and PIK3C3/VPS34 complex or indirectly promotes autophagy by regulating the expression of autophagy-related genes that ).…”

High-Fat Diet Alters the Retinal Transcriptome in the Absence of Gut Microbiota

“…High expression of CTRPs has been reported in the drusen of human donor eyes with AMD [52]. Additionally, the CTRP family has reported to mediate glucoseinduced oxidative stress and apoptosis in RPE cells [53]. Ifi204 (interferon gamma inducible protein) is a cytosolic DNA sensor involved in initiation of a type 1 interferon response and activation of the inflammasome pathway in response to bacterial or viral infection [54,55].…”