PTGER1 deletion attenuates renal injury in diabetic mouse models.

Abstract

We hypothesized that the EP1 receptor promotes renal damage in diabetic nephropathy. We rendered EP1 (PTGER1, official symbol) knockout mice (EP1(-/-)) diabetic using the streptozotocin and OVE26 models. Albuminuria, mesangial matrix expansion, and glomerular hypertrophy were each blunted in EP1(-/-) streptozotocin and OVE26 cohorts compared with wild-type counterparts. Although diabetes-associated podocyte depletion was unaffected by EP1 deletion, EP1 antagonism with ONO-8711 in cultured podocytes decreased angiotensin II-mediated superoxide generation, suggesting that EP1-associated injury of remaining podocytes in vivo could contribute to filtration barrier dysfunction. Accordingly, EP1 deletion in OVE26 mice prevented nephrin mRNA expression down-regulation and ameliorated glomerular basement membrane thickening and foot process effacement. Moreover, EP1 deletion reduced diabetes-induced expression of fibrotic markers fibronectin and α-actin, whereas EP1 antagonism decreased fibronectin in cultured proximal tubule cells. Similarly, proximal tubule megalin expression was reduced by diabetes but was preserved in EP1(-/-) mice. Finally, the diabetes-associated increase in angiotensin II-mediated constriction of isolated mesenteric arteries was blunted in OVE26EP1(-/-) mice, demonstrating a role for EP1 receptors in the diabetic vasculature. These data suggest that EP1 activation contributes to diabetic nephropathy progression at several locations, including podocytes, proximal tubule, and the vasculature. The EP1 receptor facilitates the actions of angiotensin II, thereby suggesting that targeting of both the renin-angiotensin system and the EP1 receptor could be beneficial in diabetic nephropathy.

• Authors: Jean-François Thibodeau, Rania Nasrallah, Anthony Carter, Ying He, Rhian Touyz, Richard L Hébert, Christopher R J Kennedy
• Journal: The American journal of pathology (Am J Pathol) Vol. 183 Issue 6 Pg. 1789-1802 (Dec 2013) ISSN: 1525-2191 [Electronic] United States
• PMID: 24113456 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Actins
• Bridged Bicyclo Compounds
• Caproates
• Fibronectins
• ONO 8711
• Ptger1 protein, mouse
• Receptors, Prostaglandin E, EP1 Subtype
• Superoxides
• Angiotensin II

Topics

• Actins (biosynthesis, genetics)
• Angiotensin II (genetics, metabolism)
• Animals
• Bridged Bicyclo Compounds (pharmacology)
• Caproates (pharmacology)
• Diabetes Mellitus, Experimental (genetics, metabolism, pathology)
• Diabetic Nephropathies (genetics, metabolism, pathology)
• Fibronectins (biosynthesis, genetics)
• Gene Deletion
• Gene Expression Regulation (drug effects, genetics)
• Glomerular Filtration Barrier (metabolism, pathology)
• Mesenteric Arteries (metabolism, pathology)
• Mice
• Mice, Knockout
• Receptors, Prostaglandin E, EP1 Subtype (genetics, metabolism)
• Renin-Angiotensin System (drug effects, genetics)
• Superoxides (metabolism)
• Vasoconstriction (drug effects)