TY - JOUR
T1 - Deletion of the Pedf gene leads to inflammation, photoreceptor loss and vascular disturbances in the retina
AU - Chen, Xin
AU - Xu, Manhong
AU - Zhang, Xiaomin
AU - Barnstable, Colin J.
AU - Li, Xiaorong
AU - Tombran-Tink, Joyce
N1 - Funding Information:
Our findings that systemically elevated levels of IL-2, GM-CSF and CRP in Pedf−/− mice are accompanied by invasion of monocytes, activation of glia, vascular leakage, and reduced visual sensitivity in the retina support the role of systemic inflammation in retinal diseases and suggest that these events are, in part, under the control of PEDF. These results validate our previously published work that treatment with PEDF or its bioactive peptide in diabetic retinas reduces levels of inflammatory cytokines (Liu et al., 2012), inflammation, glia activation, photoreceptor and RGC death, and vascular leakage in the retina and that it may do so through the activation of ERK1/2 and AKT signaling (Tombran-Tink and Barnstable, 2003a, 2003b; Mori et al., 2002; Hauswirth et al., 2004; Li et al., 2006; Liu et al., 2012; Cao et al., 1999, 2001). The reverse conditions are all evident in the retina when the Pedf gene is deleted, providing a convincing argument that the gene is essential to retinal homeostasis and systemic inflammation and its mechanisms of actions in both non-diseased and diabetic retinas (Liu et al., 2012) are mediated through ERK1/2 and AKT signaling, two pathways involved in multiple cellular processes.This work was supported by the National Natural Science Foundation of China (82171085), the Tianjin Postgraduate Research Innovation Project (2021YJSB271), and the National Natural Science Foundation of China (81870675).
Funding Information:
This work was supported by the National Natural Science Foundation of China ( 82171085 ), the Tianjin Postgraduate Research Innovation Project ( 2021YJSB271 ), and the National Natural Science Foundation of China ( 81870675 ).
Publisher Copyright:
© 2022 Elsevier Ltd
PY - 2022/9
Y1 - 2022/9
N2 - Retinal diseases are often accompanied by inflammation, vascular abnormalities, and neurodegeneration that decrease vision. Treatment with exogenous PEDF is widely shown to alleviate these conditions leading us to hypothesize that loss of function of the PEDF gene disrupts these pathways and leads to visual loss. Measurements were carried out by detailed phenotyping of PEDF null mice to assess expression of immunomodulators, glia activation, systemic inflammation, vascular disturbances, and visual sensitivity often associated with retinal pathologies. With a deletion of the Pedf gene, there was increased expression of several immune modulators in Pedf−/− retinas and serum with IL-2 and GM-CSF upregulated in both. Increases in retina glia activation and macrophage infiltration, levels of serum c-reactive protein (CRP), numbers of white and red blood cells and platelets and decreased blood glucose levels were all features associated with PEDF null mice. With PEDF gene deletion, there was also a notable increase in apoptosis in early developing retinas (PN3), reduced thickness of the photoreceptor layer, swelling of the inner plexiform layer, reduced retinal sensitivity and steady-state reduced activation of Erk and Akt, two signaling pathways used by PEDF. There is a substantial body of animal data emphasizing utility of PEDF treatment in homeostatic regulation of retinal diseases, including diabetic retinopathy and age-related macular degeneration but there is little agreement or evidence on the role of endogenous PEDF in retinal diseases. Our findings strongly support the concept that a deletion of the PEDF gene makes the retina vulnerable to diseases, and argue that endogenous PEDF plays a critical role in limiting pathological events in the retina.
AB - Retinal diseases are often accompanied by inflammation, vascular abnormalities, and neurodegeneration that decrease vision. Treatment with exogenous PEDF is widely shown to alleviate these conditions leading us to hypothesize that loss of function of the PEDF gene disrupts these pathways and leads to visual loss. Measurements were carried out by detailed phenotyping of PEDF null mice to assess expression of immunomodulators, glia activation, systemic inflammation, vascular disturbances, and visual sensitivity often associated with retinal pathologies. With a deletion of the Pedf gene, there was increased expression of several immune modulators in Pedf−/− retinas and serum with IL-2 and GM-CSF upregulated in both. Increases in retina glia activation and macrophage infiltration, levels of serum c-reactive protein (CRP), numbers of white and red blood cells and platelets and decreased blood glucose levels were all features associated with PEDF null mice. With PEDF gene deletion, there was also a notable increase in apoptosis in early developing retinas (PN3), reduced thickness of the photoreceptor layer, swelling of the inner plexiform layer, reduced retinal sensitivity and steady-state reduced activation of Erk and Akt, two signaling pathways used by PEDF. There is a substantial body of animal data emphasizing utility of PEDF treatment in homeostatic regulation of retinal diseases, including diabetic retinopathy and age-related macular degeneration but there is little agreement or evidence on the role of endogenous PEDF in retinal diseases. Our findings strongly support the concept that a deletion of the PEDF gene makes the retina vulnerable to diseases, and argue that endogenous PEDF plays a critical role in limiting pathological events in the retina.
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U2 - 10.1016/j.exer.2022.109171
DO - 10.1016/j.exer.2022.109171
M3 - Article
C2 - 35809620
AN - SCOPUS:85133765765
SN - 0014-4835
VL - 222
JO - Experimental Eye Research
JF - Experimental Eye Research
M1 - 109171
ER -
