Angiotensin-(1-7) Attenuates Kidney Injury Due to Obstructive Nephropathy in Rats.

Abstract

BACKGROUND:

Angiotensin-(1-7) [Ang-(1-7)] counteracts many actions of the renin-angiotensin-aldosterone system. Despite its renoprotective effects, extensive controversy exists regarding the role of Ang-(1-7) in obstructive nephropathy, which is characterized by renal tubulointerstitial fibrosis and apoptosis.

METHODS:

To examine the effects of Ang-(1-7) in unilateral ureteral obstruction (UUO), male Sprague-Dawley rats were divided into three groups: control, UUO, and Ang-(1-7)-treated UUO rats. Ang-(1-7) was continuously infused (24 μg/[kg·h]) using osmotic pumps. We also treated NRK-52E cells in vitro with Ang II (1 μM) in the presence or absence of Ang-(1-7) (1 μM), Mas receptor antagonist A779 (1 μM), and Mas receptor siRNA (50 nM) to examine the effects of Ang-(1-7) treatment on Ang II-stimulated renal injury via Mas receptor.

RESULTS:

Angiotensin II (Ang II) and angiotensin type 1 receptor (AT1R) protein expression was higher in UUO kidneys than in controls. Ang-(1-7) treatment also decreased proapoptotic protein expression in UUO kidneys. Ang-(1-7) also significantly ameliorated TUNEL positive cells in UUO kidneys. Additionally, Ang-(1-7) reduced profibrotic protein expression and decreased the increased tumor growth factor (TGF)-β1/Smad signaling present in UUO kidneys. In NRK-52E cells, Ang II induced the expression of TGF-β1/Smad signaling effectors and proapoptotic and fibrotic proteins, as well as cell cycle arrest, which were attenuated by Ang-(1-7) pretreatment. However, treatment with A779 and Mas receptor siRNA enhanced Ang II-induced apoptosis and fibrosis. Moreover, Ang II increased tumor necrosis factor-α converting enzyme (TACE) and decreased angiotensin-converting enzyme 2 (ACE2) expression in NRK-52E cells, while pretreatment with Ang-(1-7) or A779 significantly inhibited or enhanced these effects, respectively.

CONCLUSION:

Ang-(1-7) prevents obstructive nephropathy by suppressing renal apoptosis and fibrosis, possibly by regulating TGF-β1/Smad signaling and cell cycle arrest via suppression of AT1R expression. In addition, Ang-(1-7) increased and decreased ACE2 and TACE expression, respectively, which could potentially mediate a positive feedback mechanism via the Mas receptor.

• Authors: Chang Seong Kim, In Jin Kim, Eun Hui Bae, Seong Kwon Ma, JongUn Lee, Soo Wan Kim
• Journal: PloS one (PLoS One) Vol. 10 Issue 11 Pg. e0142664 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26556707 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 7-Ala-angiotensin (1-7)
• Peptide Fragments
• Receptor, Angiotensin, Type 1
• Transforming Growth Factor beta1
• Angiotensin II
• Angiotensin I
• angiotensin I (1-7)

Topics

• Angiotensin I (pharmacology, therapeutic use)
• Angiotensin II (analogs & derivatives, pharmacology)
• Animals
• Apoptosis (drug effects)
• Cell Line
• Kidney (drug effects, metabolism, pathology)
• Kidney Diseases (drug therapy, metabolism, pathology)
• Male
• Peptide Fragments (pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Receptor, Angiotensin, Type 1 (metabolism)
• Renin-Angiotensin System (drug effects)
• Signal Transduction (drug effects)
• Transforming Growth Factor beta1 (metabolism)