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

Authors Tojo A, Kinugasa S, Fujita T, Wilcox C

Received 26 June 2015

Accepted for publication 28 November 2015

Published 18 January 2016 Volume 2016:9 Pages 1—10

DOI https://doi.org/10.2147/DMSO.S91245

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Hui He

Peer reviewer comments 3

Editor who approved publication: Professor Ming-Hui Zou


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

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