Characterization of the intrarenal renin-angiotensin system in experimental alport syndrome.

Abstract

Blockade of the renin-angiotensin system attenuates the progression of experimental and clinical Alport syndrome (AS); however, the underlying mechanism(s) remains largely unknown. We evaluated the renin-angiotensin system in 4- and 7-week-old homozygous for collagen, type IV, α3 gene (Col4A3(-/-)) and wild-type mice, a model of AS characterized by proteinuria and progressive renal injury. Renal angiotensin (Ang) II levels increased, whereas renal Ang-(1-7) levels decreased in 7-week-old Col4a3(-/-) mice compared with age-matched controls; these changes were partially reversed by recombinant angiotensin-converting enzyme 2 (ACE2) treatment. The expression of both the angiotensinogen and renin protein increased in Col4a3(-/-) compared with wild-type mice. Consistent with the Ang-(1-7) levels, the expression and activity of kidney ACE2 decreased in 7-week-old Col4a3(-/-) mice. The urinary excretion rate of ACE2 paralleled the decline in tissue expression. Expression of an Ang II-induced gene, heme oxygenase-1, was up-regulated in the kidneys of 7-week-old Col4a3(-/-) mice compared with wild-type mice by microarray analysis. Heme oxygenase-1 (HO-1) protein expression was increased in kidneys of Col4a3(-/-) mice and normalized by treatment with ACE inhibitor. Urinary HO-1 excretion paralleled renal HO-1 expression. In conclusion, progressive kidney injury in AS is associated with changes in expression of intrarenal renin Ang system components and Ang peptides. HO-1 and ACE2 may represent novel markers of AS-associated kidney injury, whereas administration of recombinant ACE2 and/or Ang-(1-7) may represent novel therapeutic approaches in AS.

• Authors: Eun Hui Bae, Ana Konvalinka, Fei Fang, Xiaohua Zhou, Vanessa Williams, Nicholas Maksimowski, Xuewen Song, Shao-Ling Zhang, Rohan John, Gavin Y Oudit, York Pei, James W Scholey
• Journal: The American journal of pathology (Am J Pathol) Vol. 185 Issue 5 Pg. 1423-35 (May 2015) ISSN: 1525-2191 [Electronic] United States
• PMID: 25777062 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Membrane Proteins
• Heme Oxygenase-1
• Hmox1 protein, mouse
• Peptidyl-Dipeptidase A
• ACE2 protein, human
• Ace2 protein, mouse
• Angiotensin-Converting Enzyme 2

Topics

• Angiotensin-Converting Enzyme 2
• Animals
• Blotting, Western
• Cell Line
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Heme Oxygenase-1 (metabolism)
• Humans
• Immunohistochemistry
• Kidney (metabolism, pathology)
• Membrane Proteins (metabolism)
• Mice
• Mice, Knockout
• Nephritis, Hereditary (metabolism, pathology)
• Oligonucleotide Array Sequence Analysis
• Peptidyl-Dipeptidase A (metabolism)
• Real-Time Polymerase Chain Reaction
• Renin-Angiotensin System (physiology)