EP4 inhibition attenuates the development of diabetic and non-diabetic experimental kidney disease

Abstract The therapeutic targeting of prostanoid subtype receptors may slow the development of chronic kidney disease (CKD) through mechanisms that are distinct from those of upstream COX inhibition. Here, employing multiple experimental models of CKD, we studied the effects of inhibition of the EP4...

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Autores principales:	Karina Thieme, Syamantak Majumder, Angela S. Brijmohan, Sri N. Batchu, Bridgit B. Bowskill, Tamadher A. Alghamdi, Suzanne L. Advani, M. Golam Kabir, Youan Liu, Andrew Advani
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3c7f7c6c5c3f478c808baefc6898c731
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spelling	oai:doaj.org-article:3c7f7c6c5c3f478c808baefc6898c7312021-12-02T15:05:20ZEP4 inhibition attenuates the development of diabetic and non-diabetic experimental kidney disease10.1038/s41598-017-03237-32045-2322https://doaj.org/article/3c7f7c6c5c3f478c808baefc6898c7312017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03237-3https://doaj.org/toc/2045-2322Abstract The therapeutic targeting of prostanoid subtype receptors may slow the development of chronic kidney disease (CKD) through mechanisms that are distinct from those of upstream COX inhibition. Here, employing multiple experimental models of CKD, we studied the effects of inhibition of the EP4 receptor, one of four receptor subtypes for the prostanoid prostaglandin E2. In streptozotocin-diabetic endothelial nitric oxide synthase knockout mice, EP4 inhibition attenuated the development of albuminuria, whereas the COX inhibitor indomethacin did not. In Type 2 diabetic db/db mice, EP4 inhibition lowered albuminuria to a level comparable with that of the ACE inhibitor captopril. However, unlike captopril, EP4 inhibition had no effect on blood pressure or hyperfiltration although it did attenuate mesangial matrix accumulation. Indicating a glucose-independent mechanism of action, EP4 inhibition also attenuated proteinuria development and glomerular scarring in non-diabetic rats subjected to surgical renal mass ablation. Finally, in vitro, EP4 inhibition prevented transforming growth factor-ß1 induced dedifferentiation of glomerular podocytes. In rodent models of diabetic and non-diabetic CKD, EP4 inhibition attenuated renal injury through mechanisms that were distinct from either broadspectrum COX inhibition or “standard of care” renin angiotensin system blockade. EP4 inhibition may represent a viable repurposing opportunity for the treatment of CKD.Karina ThiemeSyamantak MajumderAngela S. BrijmohanSri N. BatchuBridgit B. BowskillTamadher A. AlghamdiSuzanne L. AdvaniM. Golam KabirYouan LiuAndrew AdvaniNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Karina Thieme Syamantak Majumder Angela S. Brijmohan Sri N. Batchu Bridgit B. Bowskill Tamadher A. Alghamdi Suzanne L. Advani M. Golam Kabir Youan Liu Andrew Advani EP4 inhibition attenuates the development of diabetic and non-diabetic experimental kidney disease
description	Abstract The therapeutic targeting of prostanoid subtype receptors may slow the development of chronic kidney disease (CKD) through mechanisms that are distinct from those of upstream COX inhibition. Here, employing multiple experimental models of CKD, we studied the effects of inhibition of the EP4 receptor, one of four receptor subtypes for the prostanoid prostaglandin E2. In streptozotocin-diabetic endothelial nitric oxide synthase knockout mice, EP4 inhibition attenuated the development of albuminuria, whereas the COX inhibitor indomethacin did not. In Type 2 diabetic db/db mice, EP4 inhibition lowered albuminuria to a level comparable with that of the ACE inhibitor captopril. However, unlike captopril, EP4 inhibition had no effect on blood pressure or hyperfiltration although it did attenuate mesangial matrix accumulation. Indicating a glucose-independent mechanism of action, EP4 inhibition also attenuated proteinuria development and glomerular scarring in non-diabetic rats subjected to surgical renal mass ablation. Finally, in vitro, EP4 inhibition prevented transforming growth factor-ß1 induced dedifferentiation of glomerular podocytes. In rodent models of diabetic and non-diabetic CKD, EP4 inhibition attenuated renal injury through mechanisms that were distinct from either broadspectrum COX inhibition or “standard of care” renin angiotensin system blockade. EP4 inhibition may represent a viable repurposing opportunity for the treatment of CKD.
format	article
author	Karina Thieme Syamantak Majumder Angela S. Brijmohan Sri N. Batchu Bridgit B. Bowskill Tamadher A. Alghamdi Suzanne L. Advani M. Golam Kabir Youan Liu Andrew Advani
author_facet	Karina Thieme Syamantak Majumder Angela S. Brijmohan Sri N. Batchu Bridgit B. Bowskill Tamadher A. Alghamdi Suzanne L. Advani M. Golam Kabir Youan Liu Andrew Advani
author_sort	Karina Thieme
title	EP4 inhibition attenuates the development of diabetic and non-diabetic experimental kidney disease
title_short	EP4 inhibition attenuates the development of diabetic and non-diabetic experimental kidney disease
title_full	EP4 inhibition attenuates the development of diabetic and non-diabetic experimental kidney disease
title_fullStr	EP4 inhibition attenuates the development of diabetic and non-diabetic experimental kidney disease
title_full_unstemmed	EP4 inhibition attenuates the development of diabetic and non-diabetic experimental kidney disease
title_sort	ep4 inhibition attenuates the development of diabetic and non-diabetic experimental kidney disease
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/3c7f7c6c5c3f478c808baefc6898c731
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EP4 inhibition attenuates the development of diabetic and non-diabetic experimental kidney disease

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