The quinic acid derivative KZ-41 prevents glucose-induced caspase-3 activation in retinal endothelial cells through an IGF-1 receptor dependent mechanism.
Retinal microaneurysms, an early disease manifestation of diabetic retinopathy, are associated with retinal endothelial cell (REC) death and macular edema. We previously demonstrated that a quinic acid (QA) analog, KZ-41, promoted REC survival by blunting stress-induced p38 MAPK activation. Herein,...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2017-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0180808&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849765122457731072 |
|---|---|
| author | Hui He Rebecca L Weir Jordan J Toutounchian Jayaprakash Pagadala Jena J Steinle Jerome Baudry Duane D Miller Charles R Yates |
| author_facet | Hui He Rebecca L Weir Jordan J Toutounchian Jayaprakash Pagadala Jena J Steinle Jerome Baudry Duane D Miller Charles R Yates |
| author_sort | Hui He |
| collection | DOAJ |
| description | Retinal microaneurysms, an early disease manifestation of diabetic retinopathy, are associated with retinal endothelial cell (REC) death and macular edema. We previously demonstrated that a quinic acid (QA) analog, KZ-41, promoted REC survival by blunting stress-induced p38 MAPK activation. Herein, we sought to expand our understanding of the pro-survival signal transduction pathways actuated by KZ-41. Using human RECs exposed to high glucose (25 mM, 72 hours), we demonstrated that KZ-41 blocks caspase-3 activation by triggering phosphorylation of the PI3K regulatory subunit (p85; Tyr458) and its downstream target Akt (Ser473). Akt signal transduction was accompanied by autophosphorylation of the receptor tyrosine kinase, insulin growth factor-1 receptor (IGF-1R). IGF-1R knockdown using either the tyrosine kinase inhibitor AG1024 or silencing RNA abolished KZ-41's pro-survival effect. Under high glucose stress, caspase-3 activation correlated with elevated ERK1/2 phosphorylation and decreased insulin receptor substrate-1 (IRS-1) levels. KZ-41 decreased ERK1/2 phosphorylation and reversed the glucose-dependent reduction in IRS-1. To gain insight into the mechanistic basis for IGF-1R activation by KZ-41, we used molecular modeling and docking simulations to explore a possible protein:ligand interaction between the IGF-1R kinase domain and KZ-41. Computational investigations suggest two possible KZ-41 binding sites within the kinase domain: a region with high homology to the insulin receptor contains one potential allosteric binding site, and another potential site on the other side of the kinase domain, near the hinge domain. These data, together with previous proof-of-concept efficacy studies demonstrating KZ-41 mitigates pathologic retinal neovascularization in the murine oxygen-induced retinopathy model, suggests that QA derivatives may offer therapeutic benefit in ischemic retinopathies. |
| format | Article |
| id | doaj-art-9269fe234af542b5aa18ddc12742acbd |
| institution | DOAJ |
| issn | 1932-6203 |
| language | English |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-9269fe234af542b5aa18ddc12742acbd2025-08-20T03:04:57ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01128e018080810.1371/journal.pone.0180808The quinic acid derivative KZ-41 prevents glucose-induced caspase-3 activation in retinal endothelial cells through an IGF-1 receptor dependent mechanism.Hui HeRebecca L WeirJordan J ToutounchianJayaprakash PagadalaJena J SteinleJerome BaudryDuane D MillerCharles R YatesRetinal microaneurysms, an early disease manifestation of diabetic retinopathy, are associated with retinal endothelial cell (REC) death and macular edema. We previously demonstrated that a quinic acid (QA) analog, KZ-41, promoted REC survival by blunting stress-induced p38 MAPK activation. Herein, we sought to expand our understanding of the pro-survival signal transduction pathways actuated by KZ-41. Using human RECs exposed to high glucose (25 mM, 72 hours), we demonstrated that KZ-41 blocks caspase-3 activation by triggering phosphorylation of the PI3K regulatory subunit (p85; Tyr458) and its downstream target Akt (Ser473). Akt signal transduction was accompanied by autophosphorylation of the receptor tyrosine kinase, insulin growth factor-1 receptor (IGF-1R). IGF-1R knockdown using either the tyrosine kinase inhibitor AG1024 or silencing RNA abolished KZ-41's pro-survival effect. Under high glucose stress, caspase-3 activation correlated with elevated ERK1/2 phosphorylation and decreased insulin receptor substrate-1 (IRS-1) levels. KZ-41 decreased ERK1/2 phosphorylation and reversed the glucose-dependent reduction in IRS-1. To gain insight into the mechanistic basis for IGF-1R activation by KZ-41, we used molecular modeling and docking simulations to explore a possible protein:ligand interaction between the IGF-1R kinase domain and KZ-41. Computational investigations suggest two possible KZ-41 binding sites within the kinase domain: a region with high homology to the insulin receptor contains one potential allosteric binding site, and another potential site on the other side of the kinase domain, near the hinge domain. These data, together with previous proof-of-concept efficacy studies demonstrating KZ-41 mitigates pathologic retinal neovascularization in the murine oxygen-induced retinopathy model, suggests that QA derivatives may offer therapeutic benefit in ischemic retinopathies.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0180808&type=printable |
| spellingShingle | Hui He Rebecca L Weir Jordan J Toutounchian Jayaprakash Pagadala Jena J Steinle Jerome Baudry Duane D Miller Charles R Yates The quinic acid derivative KZ-41 prevents glucose-induced caspase-3 activation in retinal endothelial cells through an IGF-1 receptor dependent mechanism. PLoS ONE |
| title | The quinic acid derivative KZ-41 prevents glucose-induced caspase-3 activation in retinal endothelial cells through an IGF-1 receptor dependent mechanism. |
| title_full | The quinic acid derivative KZ-41 prevents glucose-induced caspase-3 activation in retinal endothelial cells through an IGF-1 receptor dependent mechanism. |
| title_fullStr | The quinic acid derivative KZ-41 prevents glucose-induced caspase-3 activation in retinal endothelial cells through an IGF-1 receptor dependent mechanism. |
| title_full_unstemmed | The quinic acid derivative KZ-41 prevents glucose-induced caspase-3 activation in retinal endothelial cells through an IGF-1 receptor dependent mechanism. |
| title_short | The quinic acid derivative KZ-41 prevents glucose-induced caspase-3 activation in retinal endothelial cells through an IGF-1 receptor dependent mechanism. |
| title_sort | quinic acid derivative kz 41 prevents glucose induced caspase 3 activation in retinal endothelial cells through an igf 1 receptor dependent mechanism |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0180808&type=printable |
| work_keys_str_mv | AT huihe thequinicacidderivativekz41preventsglucoseinducedcaspase3activationinretinalendothelialcellsthroughanigf1receptordependentmechanism AT rebeccalweir thequinicacidderivativekz41preventsglucoseinducedcaspase3activationinretinalendothelialcellsthroughanigf1receptordependentmechanism AT jordanjtoutounchian thequinicacidderivativekz41preventsglucoseinducedcaspase3activationinretinalendothelialcellsthroughanigf1receptordependentmechanism AT jayaprakashpagadala thequinicacidderivativekz41preventsglucoseinducedcaspase3activationinretinalendothelialcellsthroughanigf1receptordependentmechanism AT jenajsteinle thequinicacidderivativekz41preventsglucoseinducedcaspase3activationinretinalendothelialcellsthroughanigf1receptordependentmechanism AT jeromebaudry thequinicacidderivativekz41preventsglucoseinducedcaspase3activationinretinalendothelialcellsthroughanigf1receptordependentmechanism AT duanedmiller thequinicacidderivativekz41preventsglucoseinducedcaspase3activationinretinalendothelialcellsthroughanigf1receptordependentmechanism AT charlesryates thequinicacidderivativekz41preventsglucoseinducedcaspase3activationinretinalendothelialcellsthroughanigf1receptordependentmechanism AT huihe quinicacidderivativekz41preventsglucoseinducedcaspase3activationinretinalendothelialcellsthroughanigf1receptordependentmechanism AT rebeccalweir quinicacidderivativekz41preventsglucoseinducedcaspase3activationinretinalendothelialcellsthroughanigf1receptordependentmechanism AT jordanjtoutounchian quinicacidderivativekz41preventsglucoseinducedcaspase3activationinretinalendothelialcellsthroughanigf1receptordependentmechanism AT jayaprakashpagadala quinicacidderivativekz41preventsglucoseinducedcaspase3activationinretinalendothelialcellsthroughanigf1receptordependentmechanism AT jenajsteinle quinicacidderivativekz41preventsglucoseinducedcaspase3activationinretinalendothelialcellsthroughanigf1receptordependentmechanism AT jeromebaudry quinicacidderivativekz41preventsglucoseinducedcaspase3activationinretinalendothelialcellsthroughanigf1receptordependentmechanism AT duanedmiller quinicacidderivativekz41preventsglucoseinducedcaspase3activationinretinalendothelialcellsthroughanigf1receptordependentmechanism AT charlesryates quinicacidderivativekz41preventsglucoseinducedcaspase3activationinretinalendothelialcellsthroughanigf1receptordependentmechanism |