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. 2022 Oct 1:306:120850.
doi: 10.1016/j.lfs.2022.120850. Epub 2022 Jul 30.

LCZ696 (sacubitril/valsartan) protects against cyclophosphamide-induced nephrotoxicity in adult male rats: Up-regulation of Apelin-13/ACE2, miR-200, and down-regulation of TGF-β/SMAD 2/3 and miR-192

Samah S Abbas  1 , Mona F Schaalan  2 , Sahar M Gebril  3 , Fatma E Hassan  4 , Maha O Mahmoud  5 , Soha O Hassanin  6
Affiliations

LCZ696 (sacubitril/valsartan) protects against cyclophosphamide-induced nephrotoxicity in adult male rats: Up-regulation of Apelin-13/ACE2, miR-200, and down-regulation of TGF-β/SMAD 2/3 and miR-192

Samah S Abbas et al. Life Sci. .

Abstract

Background: Cyclophosphamide (CP) is a widely used chemotherapeutic drug. However, the associated nephrotoxicity restricts its clinical use.

Aim: The present research was designed to study the impact of LCZ696 (LCZ); which is a combination of Sacubitril/Valsartan compared to valsartan (VAL) on CP-induced nephrotoxicity.

Main methods: Sixty adult male Wistar rats were randomly and equally assigned into 6 groups as follows: Control, LCZ (30 mg/kg, p.o.), VAL (15 mg/kg, p.o.), CP (200 mg/kg, single dose, i.p.), CP/LCZ, and CP/VAL groups. LCZ and VAL were given once daily for 6 days prior to CP (groups 5 & 6). At the end of the experiment, kidney functions, oxidants/antioxidants, inflammatory and fibrotic biomarkers in renal tissues were assessed. Further, immunohistochemical, and histomorphometric analyses were carried out.

Key findings: In comparison with CP-treated rats, LCZ resulted in a significant reduction in serum urea (26.6 %) and creatinine (63 %), moreover it decreased renal content of reactive oxygen species (ROS), zinc finger E-box-binding homeobox (ZEB)-1, SMAD2/3, plasminogen activator inhibitor (PAI)-1, fibronectin, histone deacetylase (HDAC)-4, nuclear factor-kappa B (NF-κB) and miR-192 expression by ~40-60 % as well as the immunohistological expressions of transforming growth factor-β (TGF-β) and anti-phospho Histone (H2AX) by ~75 % reduction. Whereas the renal total antioxidant capacity (TAC), apelin-13, miR-200 expression, and the immunoreactivity of angiotensin-converting enzyme 2 (ACE2) were enhanced by ~3-4-folds. Noteworthy, the prophylactic effect of LCZ was superior to VAL on the histomorphometric and immunohistological levels.

Significance: Prophylactic administration of LCZ protected against CP-induced nephrotoxicity via up-regulating apelin-13/ACE2, miR-200, and down-regulating TGF-β/SMAD 2/3 and miR-192.

Keywords: ACE-2; Apelin-13; Cyclophosphamide; LCZ696; Nephrotoxicity; miR-200/192.

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