TPL2 (Therapeutic Targeting Tumor Progression Locus-2)/ATF4 (Activating Transcription Factor-4)/SDF1α (Chemokine Stromal Cell-Derived Factor-α) Axis Suppresses Diabetic Retinopathy

De-Wei Lai; Keng-Hung Lin; Wayne Huey-Herng Sheu; Maw-Rong Lee; Chung-Yu Chen; Wen-Jane Lee; Yi-Wen Hung; Chin-Chang Shen; Tsung-Ju Chung; Shing-Hwa Liu; Meei-Ling Sheu

doi:10.1161/CIRCRESAHA.117.311066

TPL2 (Therapeutic Targeting Tumor Progression Locus-2)/ATF4 (Activating Transcription Factor-4)/SDF1α (Chemokine Stromal Cell-Derived Factor-α) Axis Suppresses Diabetic Retinopathy

Circ Res. 2017 Sep 1;121(6):e37-e52. doi: 10.1161/CIRCRESAHA.117.311066. Epub 2017 Jul 19.

Authors

Affiliations

¹ From the Institute of Biomedical Sciences (D.-W.L., M.-L.S.), Department of Chemistry (M.-R.L., C.-Y.C.), Rong Hsing Research Center for Translational Medicine (K.-H.L., W.H.-H.S., M.-L.S.), National Chung Hsing University, Taichung, Taiwan; Department of Ophthalmology (K.-H.L.), Division of Endocrinology and Metabolism (W.H.-H.S.), and Department of Medical Research (W.-J.L., Y.-W.H., M.-L.S.), Taichung Veterans General Hospital, Taiwan; Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan, Taiwan (C.-C.S.); Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (T.-J.C.); Department of Internal Medicine, Armed Forces Taichung General Hospital, Taiwan (T.-J.C.); Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan (S.-H.L.); and Institute of Toxicology, College of Medicine, National Taiwan University, Taipei (S.-H.L.).
² From the Institute of Biomedical Sciences (D.-W.L., M.-L.S.), Department of Chemistry (M.-R.L., C.-Y.C.), Rong Hsing Research Center for Translational Medicine (K.-H.L., W.H.-H.S., M.-L.S.), National Chung Hsing University, Taichung, Taiwan; Department of Ophthalmology (K.-H.L.), Division of Endocrinology and Metabolism (W.H.-H.S.), and Department of Medical Research (W.-J.L., Y.-W.H., M.-L.S.), Taichung Veterans General Hospital, Taiwan; Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan, Taiwan (C.-C.S.); Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (T.-J.C.); Department of Internal Medicine, Armed Forces Taichung General Hospital, Taiwan (T.-J.C.); Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan (S.-H.L.); and Institute of Toxicology, College of Medicine, National Taiwan University, Taipei (S.-H.L.). mlsheu@nchu.edu.tw.

PMID: 28724746
DOI: 10.1161/CIRCRESAHA.117.311066

Abstract

Rationale: Diabetic retinopathy is characterized by vasopermeability, vascular leakage, inflammation, blood-retinal barrier breakdown, capillary degeneration, and neovascularization. However, the mechanisms underlying the association between diabetes mellitus and progression retinopathy remain unclear.

Objective: TPL2 (tumor progression locus 2), a serine-threonine protein kinase, exerts a pathological effect on vascular angiogenesis. This study investigated the role of N^ε-(carboxymethyl)lysine, a major advanced glycation end products, and the involved TPL2-related molecular signals in diabetic retinopathy using models of in vitro and in vivo and human samples.

Methods and results: Serum N^ε-(carboxymethyl)lysine levels and TPL2 kinase activity were significantly increased in clinical patients and experimental animals with diabetic retinopathy. Intravitreal administration of pharmacological blocker or neutralizing antibody inhibited TPL2 and effectively suppressed the pathological characteristics of retinopathy in streptozotocin-induced diabetic animal models. Intravitreal VEGF (vascular endothelial growth factor) neutralization also suppressed the diabetic retinopathy in diabetic animal models. Mechanistic studies in primary human umbilical vein endothelial cells and primary retinal microvascular endothelial cells from streptozotocin-diabetic rats, db/db mice, and samples from patients with diabetic retinopathy revealed a positive parallel correlation between N^ε-(carboxymethyl)lysine and the TPL2/chemokine SDF1α (stromal cell-derived factor-α) axis that is dependent on endoplasmic reticulum stress-related molecules, especially ATF4 (activating transcription factor-4).

Conclusions: This study demonstrates that inhibiting the N^ε-(carboxymethyl)lysine-induced TPL2/ATF4/SDF1α axis can effectively prevent diabetes mellitus-mediated retinal microvascular dysfunction. This signaling axis may include the therapeutic potential for other diseases involving pathological neovascularization or macular edema.

Keywords: ATF4; ER stress; Nε-(Carboxymethyl)-L-lysine; SDF1α; TPL2; VEGF; diabetic retinopathy.

MeSH terms

Activating Transcription Factor 4 / metabolism*
Animals
Cells, Cultured
Chemokine CXCL12 / metabolism*
Diabetes Mellitus, Experimental / metabolism
Diabetic Retinopathy / metabolism*
Human Umbilical Vein Endothelial Cells / metabolism
Humans
Lysine / analogs & derivatives
Lysine / blood
MAP Kinase Kinase Kinases / metabolism*
Mice
Mice, Inbred C57BL
Rats
Rats, Sprague-Dawley
Signal Transduction

Substances

Chemokine CXCL12
Activating Transcription Factor 4
N(6)-carboxymethyllysine
MAP Kinase Kinase Kinases
Lysine