Skip to main page content
U.S. flag
See More

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Dec 15;9(12):5473-5484.
eCollection 2017.

LCZ696 (Sacubitril/valsartan) ameliorates oxidative stress, inflammation, fibrosis and improves renal function beyond angiotensin receptor blockade in CKD

Wanghui Jing  1   2 , Nosratola D Vaziri  1 , Ane Nunes  1 , Yasunori Suematsu  1 , Ted Farzaneh  3 , Mahyar Khazaeli  1 , Hamid Moradi  1   4
Affiliations

LCZ696 (Sacubitril/valsartan) ameliorates oxidative stress, inflammation, fibrosis and improves renal function beyond angiotensin receptor blockade in CKD

Wanghui Jing et al. Am J Transl Res. .

Abstract

Progressive deterioration of kidney function in chronic kidney disease (CKD) is mediated by hypertension, oxidative stress, inflammation, and fibrosis. Renin-angiotensin blockade is commonly used to retard CKD progression. In addition, vasoactive peptides have been shown to reduce blood pressure and exert antioxidant, anti-inflammatory and anti-fibrotic effects. We hypothesized that administration of LCZ696 (sacubitril/valsartan) is more effective than valsartan alone in slowing progression of CKD. Male Sprague Dawley rats underwent sham surgery or 5/6 nephrectomy and after two weeks the CKD animals were randomized to no treatment, valsartan (30 mg/kg), or LCZ696 (60 mg/kg) daily by gavage. Serum, urine and kidney tissue analyses were performed after 8 weeks. The untreated CKD rats exhibited hypertension, proteinuria, tubular and glomerular damage, upregulation of pro-inflammatory, pro-oxidant and pro-fibrotic pathways; reduction in nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its key target products. LCZ696 administration improved renal function and histology and attenuated most of the molecular markers of oxidative stress, inflammation and fibrosis. Furthermore, LCZ696 was more effective than valsartan therapy alone in delaying the progression of kidney disease. Future clinical trials are needed to determine the safety and efficacy of this agent in treatment of patients with CKD.

Keywords: Chronic kidney disease; LCZ696; fibrosis; inflammation; natriuretic peptides; oxidative stress.

PubMed Disclaimer

Conflict of interest statement

None.

Figures

Figure 1
Figure 1
Representative photomicrographs of the H&E and Trichrome stained kidney sections in control (n=6), CKD (n=9), LCZ (n=12) and VAL (n=12) treated animals. Data depicting glomerulosclerosis index and tubulointerstitial injury in different groups. Data are mean ± SEM. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.
Figure 2
Figure 2
Impact of LCZ and VAL on oxidative stress pathway. Representative Western blots and group data depicting eNOS, NAD(P)H oxidase subunits (NOX-4 and Gp91phox), nitrotyrosine and MPO in the renal tissues of the control rats (n=6), CKD rats (n=9), CKD rats treated with LCZ (n=9), and CKD rats treated with VAL (n=9). Data are mean ± SEM. *P<0.05, **P<0.01, ***P<0.001. GAPDH was used as a loading control. (Please see the Figure S1 for uncropped images of the blots).
Figure 3
Figure 3
Impact of LCZ and VAL on inflammatory pathway. Representative Western blots and group data depicting nuclear content of p65 active subunit of NF-κB and protein abundance of MCP-1, iNOS and COX-2 in the renal tissues of the control rats (n=6), CKD rats (n=9), CKD rats treated with LCZ (n=9), and CKD rats treated with VAL (n=9). Data are mean ± SEM. *P<0.05, **P<0.01, ***P<0.001.Histone was used as a loading control for nuclear extracts. GAPDH was used as a loading control for cytoplasmic extracts. (Please see the Figure S2 for uncropped images of the blots).
Figure 4
Figure 4
Impact of LCZ and VAL on Nrf2 pathway. Representative Western blots and group data depicting nuclear translocation of Nrf2 and protein abundances of its repressor Keap1 and downstream gene products, Cu/Zn-SOD, catalase, GPX and HO-1 in the renal tissues of the control rats (n=6), CKD rats (n=9), CKD rats treated with LCZ (n=9), and CKD rats treated with VAL (n=9). Data are mean ± SEM. *P<0.05, **P<0.01, ***P<0.001. Histone was used as a loading control for nuclear extracts. GAPDH was used as a loading control for cytoplasmic extracts. (Please see the Figure S3 for uncropped images of the blots).
Figure 5
Figure 5
Impact of LCZ and VAL on fibrosis pathway. Representative Western blots and group data depicting TGF-β, α-SM actin, and PAI-1 abundance in the renal tissues of the control rats (n=6), CKD rats (n=9), CKD rats treated with LCZ (n=9), and CKD rats treated with VAL (n=9). Data are mean ± SEM. *P<0.05, **P<0.01, ***P<0.001. GAPDH was used as a loading control for cytoplasmic extracts. (Please see the Figure S4 for uncropped images of the blots).
See this image and copyright information in PMC

References

    1. Paloian NJ, Giachelli CM. A current understanding of vascular calcification in CKD. Am J Physiol Renal Physiol. 2014;307:F891–900. - PMC - PubMed
    1. Kovesdy CP, Kalantar-Zadeh K. Enter the dragon: a Chinese epidemic of chronic kidney disease? Lancet. 2012;379:783–785. - PubMed
    1. Zhang L, Wang F, Wang L, Wang W, Liu B, Liu J, Chen M, He Q, Liao Y, Yu X, Chen N, Zhang JE, Hu Z, Liu F, Hong D, Ma L, Liu H, Zhou X, Chen J, Pan L, Chen W, Wang W, Li X, Wang H. Prevalence of chronic kidney disease in China: a cross-sectional survey. Lancet. 2012;379:815–822. - PubMed
    1. Vaziri ND. Oxidative stress in uremia: nature, mechanisms, and potential consequences. Semin Nephrol. 2004;24:469–473. - PubMed
    1. Himmelfarb J. Linking oxidative stress and inflammation in kidney disease: which is the chicken and which is the egg? Semin Dial. 2004;17:449–454. - PubMed