Projects per year
Abstract
Background and purpose: This study investigated the reno-protective effects of a highly selective AT2R agonist peptide, β-Pro7Ang III in a mouse model of acute kidney injury (AKI). Methods: C57BL/6 J mice underwent either sham surgery or unilateral kidney ischemia-reperfusion injury (IRI) for 40 min. IRI mice were treated with either β-Pro7Ang III or perindopril and at 7 days post-surgery the kidneys analysed for histopathology and the development of fibrosis and matrix metalloproteinase (MMP)-2 and -9 activity. The association of the therapeutic effects of β-Pro7Ang III with macrophage number and phenotype was determined in vivo and in vitro. Key results: Decreased kidney tubular injury, interstitial matrix expansion and reduced interstitial immune cell infiltration in IRI mice receiving β-Pro7Ang III treatment was observed at day 7, compared to IRI mice without treatment. This correlated to reduced collagen accumulation and MMP-2 activity in IRI mice following β-Pro7Ang III treatment. FACS analysis showed a reduced number and proportion of CD45+CD11b+F4/80+ macrophages in IRI kidneys in response to β-Pro7Ang III, correlating with a significant increase in M2 macrophage markers and decreased M1 markers at day 3 and 7 post-IR injury, respectively. In vitro analysis of cultured THP-1 cells showed that β-Pro7Ang III attenuated lipopolysaccharide (LPS)-induced tumour necrosis factor-α (TNF-α) and interleukin (IL)− 6 production but increased IL-10 secretion, compared to LPS alone. Conclusion: Administration of β-Pro7Ang III via mini-pump improved kidney structure and reduced interstitial collagen accumulation, in parallel with an alteration of macrophage phenotype and anti-inflammatory cytokine release, therefore mitigating the downstream progression of ischemic AKI.
Original language | English |
---|---|
Article number | 114556 |
Number of pages | 13 |
Journal | Biomedicine & Pharmacotherapy |
Volume | 161 |
Issue number | 114556 |
DOIs | |
Publication status | Published - May 2023 |
Keywords
- Acute kidney injury
- ATR agonist
- Fibrosis
- Ischemia-reperfusion injury
- Macrophage phenotype
- Macrophages
- Metalloproteinase
- Renin-angiotensin system
Projects
- 1 Finished
-
Novel treatments of fibrosis for hypertensive heart disease
Widdop, R., Aguilar, M. & Denton, K.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/17 → 31/12/20
Project: Research
Equipment
-
FlowCore
Andrew Fryga (Manager)
Faculty of Medicine Nursing and Health Sciences Research PlatformsFacility/equipment: Facility
-
Histology Platform
Camilla Cohen (Manager)
Faculty of Medicine Nursing and Health Sciences Research PlatformsFacility/equipment: Facility
-
Monash Micro Imaging
Stephen Firth (Manager), Alex Fulcher (Operator), Oleks Chernyavskiy (Operator), Margaret Rzeszutek (Other), David Potter (Manager), Volker Hilsenstein (Operator), Juan Nunez-Iglesias (Other), Stephen Cody (Manager), Irena Carmichael (Operator), Betty Kouskousis (Other), Sarah Creed (Manager) & Giulia Ballerin (Operator)
Faculty of Medicine Nursing and Health Sciences Research PlatformsFacility/equipment: Facility