A local renal renin–angiotensin system activation via renal uptake of prorenin and angiotensinogen in diabetic rats

A local renal renin–angiotensin system activation via renal uptake of prorenin and angiotensinogen in diabetic rats

Akihiro Tojo,1 Satoshi Kinugasa,1 Toshiro Fujita,2 Christopher S Wilcox3 1Division of Nephrology and Endocrinology, 2Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan; 3Division of Nephrology and Hypertension, Center for Hypertension, Kidney and Vascular Rese...

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Autores principales: Tojo A, Kinugasa S, Fujita T, Wilcox CS
Formato: article
Lenguaje:EN
Publicado: Dove Medical Press 2016
Materias:
renal renin angiotensin system
prorenin
angiotensinogen
diabetic nephropathy
microalbuminuria
Specialties of internal medicine
RC581-951
Acceso en línea:https://doaj.org/article/4f2bfed4bf5e482f9787671e6d28708b
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spelling oai:doaj.org-article:4f2bfed4bf5e482f9787671e6d28708b2021-12-02T00:36:26ZA local renal renin–angiotensin system activation via renal uptake of prorenin and angiotensinogen in diabetic rats1178-7007https://doaj.org/article/4f2bfed4bf5e482f9787671e6d28708b2016-01-01T00:00:00Zhttps://www.dovepress.com/a-local-renal-reninndashangiotensin-system-activation-via-renal-uptake-peer-reviewed-article-DMSOhttps://doaj.org/toc/1178-7007Akihiro Tojo,1 Satoshi Kinugasa,1 Toshiro Fujita,2 Christopher S Wilcox3 1Division of Nephrology and Endocrinology, 2Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan; 3Division of Nephrology and Hypertension, Center for Hypertension, Kidney and Vascular Research, Georgetown University, Washington, DC, USA Abstract: The mechanism of activation of local renal renin–angiotensin system (RAS) has not been clarified in diabetes mellitus (DM). We hypothesized that the local renal RAS will be activated via increased glomerular filtration and tubular uptake of prorenin and angiotensinogen in diabetic kidney with microalbuminuria. Streptozotocin (STZ)-induced DM and control rats were injected with human prorenin and subsequently with human angiotensinogen. Human prorenin uptake was increased in podocytes, proximal tubules, macula densa, and cortical collecting ducts of DM rats where prorenin receptor (PRR) was expressed. Co-immunoprecipitation of kidney homogenates in DM rats revealed binding of human prorenin to the PRR and to megalin. The renal uptake of human angiotensinogen was increased in DM rats at the same nephron sites as prorenin. Angiotensin-converting enzyme was increased in podocytes, but decreased in the proximal tubules in DM rats, which may have contributed to unchanged renal levels of angiotensin despite increased angiotensinogen. The systolic blood pressure increased more after the injection of 20 µg of angiotensinogen in DM rats than in controls, accompanied by an increased uptake of human angiotensinogen in the vascular endothelium. In conclusion, endocytic uptake of prorenin and angiotensinogen in the kidney and vasculature in DM rats was contributed to increased tissue RAS and their pressor response to angiotensinogen. Keywords: renal renin–angiotensin system, prorenin, angiotensinogen, diabetic nephropathy, microalbuminuriaTojo AKinugasa SFujita TWilcox CSDove Medical Pressarticlerenal renin angiotensin systemproreninangiotensinogendiabetic nephropathymicroalbuminuriaSpecialties of internal medicineRC581-951ENDiabetes, Metabolic Syndrome and Obesity: Targets and Therapy, Vol 2016, Iss Issue 1, Pp 1-10 (2016)
institution DOAJ
collection DOAJ
language EN
topic renal renin angiotensin system
prorenin
angiotensinogen
diabetic nephropathy
microalbuminuria
Specialties of internal medicine
RC581-951
spellingShingle renal renin angiotensin system
prorenin
angiotensinogen
diabetic nephropathy
microalbuminuria
Specialties of internal medicine
RC581-951
Tojo A
Kinugasa S
Fujita T
Wilcox CS
A local renal renin–angiotensin system activation via renal uptake of prorenin and angiotensinogen in diabetic rats
description Akihiro Tojo,1 Satoshi Kinugasa,1 Toshiro Fujita,2 Christopher S Wilcox3 1Division of Nephrology and Endocrinology, 2Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan; 3Division of Nephrology and Hypertension, Center for Hypertension, Kidney and Vascular Research, Georgetown University, Washington, DC, USA Abstract: The mechanism of activation of local renal renin–angiotensin system (RAS) has not been clarified in diabetes mellitus (DM). We hypothesized that the local renal RAS will be activated via increased glomerular filtration and tubular uptake of prorenin and angiotensinogen in diabetic kidney with microalbuminuria. Streptozotocin (STZ)-induced DM and control rats were injected with human prorenin and subsequently with human angiotensinogen. Human prorenin uptake was increased in podocytes, proximal tubules, macula densa, and cortical collecting ducts of DM rats where prorenin receptor (PRR) was expressed. Co-immunoprecipitation of kidney homogenates in DM rats revealed binding of human prorenin to the PRR and to megalin. The renal uptake of human angiotensinogen was increased in DM rats at the same nephron sites as prorenin. Angiotensin-converting enzyme was increased in podocytes, but decreased in the proximal tubules in DM rats, which may have contributed to unchanged renal levels of angiotensin despite increased angiotensinogen. The systolic blood pressure increased more after the injection of 20 µg of angiotensinogen in DM rats than in controls, accompanied by an increased uptake of human angiotensinogen in the vascular endothelium. In conclusion, endocytic uptake of prorenin and angiotensinogen in the kidney and vasculature in DM rats was contributed to increased tissue RAS and their pressor response to angiotensinogen. Keywords: renal renin–angiotensin system, prorenin, angiotensinogen, diabetic nephropathy, microalbuminuria
format article
author Tojo A
Kinugasa S
Fujita T
Wilcox CS
author_facet Tojo A
Kinugasa S
Fujita T
Wilcox CS
author_sort Tojo A
title A local renal renin–angiotensin system activation via renal uptake of prorenin and angiotensinogen in diabetic rats
title_short A local renal renin–angiotensin system activation via renal uptake of prorenin and angiotensinogen in diabetic rats
title_full A local renal renin–angiotensin system activation via renal uptake of prorenin and angiotensinogen in diabetic rats
title_fullStr A local renal renin–angiotensin system activation via renal uptake of prorenin and angiotensinogen in diabetic rats
title_full_unstemmed A local renal renin–angiotensin system activation via renal uptake of prorenin and angiotensinogen in diabetic rats
title_sort local renal renin–angiotensin system activation via renal uptake of prorenin and angiotensinogen in diabetic rats
publisher Dove Medical Press
publishDate 2016
url https://doaj.org/article/4f2bfed4bf5e482f9787671e6d28708b
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