Glyceraldehyde-Derived Pyridinium Evokes Renal Tubular Cell Damage via RAGE Interaction

Glyceraldehyde-derived advanced glycation end products (glycer-AGEs) contribute to proximal tubulopathy in diabetes. However, what glycer-AGE structure could evoke tubular cell damage remains unknown. We first examined if deleterious effects of glycer-AGEs on reactive oxygen species (ROS) generation...

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Main Authors: Ami Sotokawauchi, Nobutaka Nakamura, Takanori Matsui, Yuichiro Higashimoto, Sho-ichi Yamagishi
Format: Article
Language:English
Published: MDPI AG 2020-04-01
Series:International Journal of Molecular Sciences
Subjects:
Online Access:https://www.mdpi.com/1422-0067/21/7/2604
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author Ami Sotokawauchi
Nobutaka Nakamura
Takanori Matsui
Yuichiro Higashimoto
Sho-ichi Yamagishi
author_facet Ami Sotokawauchi
Nobutaka Nakamura
Takanori Matsui
Yuichiro Higashimoto
Sho-ichi Yamagishi
author_sort Ami Sotokawauchi
collection DOAJ
description Glyceraldehyde-derived advanced glycation end products (glycer-AGEs) contribute to proximal tubulopathy in diabetes. However, what glycer-AGE structure could evoke tubular cell damage remains unknown. We first examined if deleterious effects of glycer-AGEs on reactive oxygen species (ROS) generation in proximal tubular cells were blocked by DNA-aptamer that could bind to glyceraldehyde-derived pyridinium (GLAP) (GLAP-aptamer), and then investigated whether and how GLAP caused proximal tubular cell injury. GLAP-aptamer and AGE-aptamer raised against glycer-AGEs were prepared using a systemic evolution of ligands by exponential enrichment. The binding affinity of GLAP-aptamer to glycer-AGEs was measured with a bio-layer interferometry. ROS generation was evaluated using fluorescent probes. Gene expression was analyzed by reverse transcription-polymerase chain reaction (RT-PCR). GLAP-aptamer bound to glycer-AGEs with a dissociation constant of 7.7 × 10<sup>−5</sup> M. GLAP-aptamer, glycer-AGE-aptamer, or antibodies directed against receptor for glycer-AGEs (RAGE) completely prevented glycer-AGE- or GLAP-induced increase in ROS generation, MCP-1, PAI-1, or RAGE gene expression in tubular cells. Our present results suggest that GLAP is one of the structurally distinct glycer-AGEs, which may mediate oxidative stress and inflammatory reactions in glycer-AGE-exposed tubular cells. Blockade of the interaction of GLAP-RAGE by GLAP-aptamer may be a therapeutic target for proximal tubulopathy in diabetic nephropathy.
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spelling doaj.art-25de97cfa2194add86503108ee1158662023-11-19T21:05:45ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-04-01217260410.3390/ijms21072604Glyceraldehyde-Derived Pyridinium Evokes Renal Tubular Cell Damage via RAGE InteractionAmi Sotokawauchi0Nobutaka Nakamura1Takanori Matsui2Yuichiro Higashimoto3Sho-ichi Yamagishi4Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume 830-0011, JapanDepartment of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume 830-0011, JapanDepartment of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume 830-0011, JapanDepartment of Chemistry, Kurume University School of Medicine, Kurume 830-0011, JapanDivision of Diabetes, Metabolism, and Endocrinology, Department of Medicine, Showa University School of Medicine, Tokyo 142-8666, JapanGlyceraldehyde-derived advanced glycation end products (glycer-AGEs) contribute to proximal tubulopathy in diabetes. However, what glycer-AGE structure could evoke tubular cell damage remains unknown. We first examined if deleterious effects of glycer-AGEs on reactive oxygen species (ROS) generation in proximal tubular cells were blocked by DNA-aptamer that could bind to glyceraldehyde-derived pyridinium (GLAP) (GLAP-aptamer), and then investigated whether and how GLAP caused proximal tubular cell injury. GLAP-aptamer and AGE-aptamer raised against glycer-AGEs were prepared using a systemic evolution of ligands by exponential enrichment. The binding affinity of GLAP-aptamer to glycer-AGEs was measured with a bio-layer interferometry. ROS generation was evaluated using fluorescent probes. Gene expression was analyzed by reverse transcription-polymerase chain reaction (RT-PCR). GLAP-aptamer bound to glycer-AGEs with a dissociation constant of 7.7 × 10<sup>−5</sup> M. GLAP-aptamer, glycer-AGE-aptamer, or antibodies directed against receptor for glycer-AGEs (RAGE) completely prevented glycer-AGE- or GLAP-induced increase in ROS generation, MCP-1, PAI-1, or RAGE gene expression in tubular cells. Our present results suggest that GLAP is one of the structurally distinct glycer-AGEs, which may mediate oxidative stress and inflammatory reactions in glycer-AGE-exposed tubular cells. Blockade of the interaction of GLAP-RAGE by GLAP-aptamer may be a therapeutic target for proximal tubulopathy in diabetic nephropathy.https://www.mdpi.com/1422-0067/21/7/2604GLAPRAGEdiabetic nephropathyproximal tubular cells
spellingShingle Ami Sotokawauchi
Nobutaka Nakamura
Takanori Matsui
Yuichiro Higashimoto
Sho-ichi Yamagishi
Glyceraldehyde-Derived Pyridinium Evokes Renal Tubular Cell Damage via RAGE Interaction
International Journal of Molecular Sciences
GLAP
RAGE
diabetic nephropathy
proximal tubular cells
title Glyceraldehyde-Derived Pyridinium Evokes Renal Tubular Cell Damage via RAGE Interaction
title_full Glyceraldehyde-Derived Pyridinium Evokes Renal Tubular Cell Damage via RAGE Interaction
title_fullStr Glyceraldehyde-Derived Pyridinium Evokes Renal Tubular Cell Damage via RAGE Interaction
title_full_unstemmed Glyceraldehyde-Derived Pyridinium Evokes Renal Tubular Cell Damage via RAGE Interaction
title_short Glyceraldehyde-Derived Pyridinium Evokes Renal Tubular Cell Damage via RAGE Interaction
title_sort glyceraldehyde derived pyridinium evokes renal tubular cell damage via rage interaction
topic GLAP
RAGE
diabetic nephropathy
proximal tubular cells
url https://www.mdpi.com/1422-0067/21/7/2604
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AT takanorimatsui glyceraldehydederivedpyridiniumevokesrenaltubularcelldamageviarageinteraction
AT yuichirohigashimoto glyceraldehydederivedpyridiniumevokesrenaltubularcelldamageviarageinteraction
AT shoichiyamagishi glyceraldehydederivedpyridiniumevokesrenaltubularcelldamageviarageinteraction