1. Contributions of Sodium-Hydrogen Exchanger 1 and Mitogen-Activated Protein Kinases to Enhanced Retinal Venular Constriction to Endothelin-1 in Diabetes
- Author
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Robert H. Rosa, Yi Ren, Lih Kuo, Yen-Lin Chen, and Travis W. Hein
- Subjects
Male ,MAPK/ERK pathway ,Complications ,Pyridines ,Swine ,Endocrinology, Diabetes and Metabolism ,p38 mitogen-activated protein kinases ,Pharmacology ,p38 Mitogen-Activated Protein Kinases ,Diabetes Mellitus, Experimental ,chemistry.chemical_compound ,Internal Medicine ,Extracellular ,Animals ,Protein kinase C ,Diabetic Retinopathy ,Sodium-Hydrogen Exchanger 1 ,Endothelin-1 ,Cariporide ,Chemistry ,Kinase ,Imidazoles ,Retinal ,Retinal Vein ,Endothelin 1 ,Vasoconstriction ,cardiovascular system ,Calcium ,Mitogen-Activated Protein Kinases ,Diabetic Angiopathies ,Signal Transduction - Abstract
Diabetes elevates endothelin-1 (ET-1) in the vitreous and enhances constriction of retinal venules to this peptide. However, mechanisms contributing to ET-1–induced constriction of retinal venules are incompletely understood. We examined roles of sodium-hydrogen exchanger 1 (NHE1), protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), and extracellular calcium (Ca2+) in retinal venular constriction to ET-1 and the impact of diabetes on these signaling molecules. Retinal venules were isolated from control pigs and pigs with streptozocin-induced diabetes for in vitro studies. ET-1–induced vasoconstriction was abolished in the absence of extracellular Ca2+ and sensitive to c-Jun N-terminal kinase (JNK) inhibitor SP600125 but unaffected by extracellular signal–regulated kinase (ERK) inhibitor PD98059, p38 kinase inhibitor SB203580, or broad-spectrum PKC inhibitor Gö 6983. Diabetes (after 2 weeks) enhanced venular constriction to ET-1, which was insensitive to PD98059 and Gö 6983 but was prevented by NHE1 inhibitor cariporide, SB203580, and SP600125. In conclusion, extracellular Ca2+ entry and activation of JNK, independent of ERK and PKC, mediate constriction of retinal venules to ET-1. Diabetes activates p38 MAPK and NHE1, which cause enhanced venular constriction to ET-1. Treatments targeting these vascular molecules may lessen retinal complications in early diabetes.
- Published
- 2021