Renal protective effects and mechanisms of the angiotensin receptor-neprilysin inhibitor LCZ696 in mice with cardiorenal syndrome.

Abstract

AIMS:

This study investigated the renal protective effects and mechanisms of angiotensin receptor-neprilysin inhibitor LCZ696 in mice with cardiorenal syndrome.

MATERIALS AND METHODS:

Mice were divided into abdominal aortic ligation alone, or treatment with LCZ696 or valsartan, whilst those undergoing sham surgery served as controls. Rat proximal renal tubular epithelial cells from the NRK-52E line were treated with control solution, LCZ696 or valsartan, in the presence or absence of Ang II for 24 h.

KEY FINDINGS:

Compared to controls, abdominal aortic ligation significantly increased plasma NT-proBNP and urine neutrophil gelatinase-associated lipocalin (NGAL), which were associated with reduced renal length and velocity time integral on ultrasonography. Histology revealed wrinkling of the glomerular capillary wall and sclerosis of the glomerulus, dilatation of the Bowman's capsule, accompanied by diffuse renal tubular atrophy and fibrosis, accompanied by lower kidney index and higher percentage area of fibrosis. Increases in NGAL and decreased ANP protein and mRNA expression levels were observed. These abnormalities were significantly prevented by LCZ696 and to a lesser extent by valsartan. Cellular experiments demonstrated a central role of Ang II/transforming growth factor-β1/Smad2/3/connective tissue growth factor-dependent signaling leading to type IV collagen deposition. This upregulation was reversed by LCZ696 in a greater extent than valsartan treatment alone, accompanied by a significant improvement in NGAL.

SIGNIFICANCE:

LCZ696 can reduce kidney injury to a level beyond valsartan therapy alone in mice with cardiorenal syndrome, which can be speculated by effects on epithelial-mesenchymal transition and fibrosis through downregulating the TGF-β1/Smad2/3/CTGF/Collagen IV pathway.

• Authors: Ying Li, Li Kang, Kai Rong, Yue Zhang, Ya Suo, Meng Yuan, Qiankun Bao, Shuai Shao, Gary Tse, Rong Li, Tong Liu, Guangping Li
• Journal: Life sciences (Life Sci) Vol. 280 Pg. 119692 (Sep 01 2021) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 34102189 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Aminobutyrates
• Angiotensin Receptor Antagonists
• Biphenyl Compounds
• Drug Combinations
• Protective Agents
• Valsartan
• sacubitril and valsartan sodium hydrate drug combination

Topics

• Aminobutyrates (pharmacology, therapeutic use)
• Angiotensin Receptor Antagonists (pharmacology, therapeutic use)
• Animals
• Biphenyl Compounds (pharmacology, therapeutic use)
• Cardio-Renal Syndrome (drug therapy, pathology)
• Cell Line
• Drug Combinations
• Kidney (drug effects, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Protective Agents (pharmacology, therapeutic use)
• Rats
• Valsartan (pharmacology, therapeutic use)