Angiotensin (1-7) Attenuates Sepsis-Induced Acute Kidney Injury by Regulating the NF-κB Pathway.

Ying Zhu,Fang Deng,Jian Li,Chenyu Zhang,Jing Chu,Yonglin Yan,Daliang Xu

doi:10.3389/fphar.2021.601909

Ying Zhu, Fang Deng + Show 5 more

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https://doi.org/10.3389/fphar.2021.601909

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Abstract

This study explores the protective mechanism of angiotensin (1-7) [Ang-(1-7)] on kidneys by examining its effects on renal histomorphology, inflammatory response, oxidative stress, and NF-κB signaling in mice suffering from sepsis-induced acute kidney injury. A sepsis-induced acute kidney injury mouse model was established by intracervically injecting lipopolysaccharides (LPS group), followed by the administration of Ang-(1-7) [LPS + Ang-(1-7) group]. The serum levels of urea nitrogen, creatinine and cystatin. c were measured with an automatic biochemical analyzer, and changes in proinflammatory cytokines and angiotensin II (Ang II) in the serum and kidneys were quantified by enzyme-linked immunosorbent assays. Changes in oxidative stress indices in the renal cortex were detected by colorimetry. The localization of Ang II in kidneys was examined by immunohistochemistry. Western blotting was used to examine phosphorylated NF-κB-p65 and IκBα levels in kidneys. Compared with the control group, the serum levels of urea nitrogen, creatinine and cystatin. c were increased, whereas the levels of Ang II, TNFα, IL-1β, IL-6, and malondialdehyde (mda) were increased significantly. The levels of Ang II and phosphorylated NF-κB-p65 were elevated in kidneys, whereas the levels of superoxide dismutase (sod), Total antioxidative capacity (TAOC), and inhibitor of NF-κB (IκBα) were reduced in the LPS group (p < 0.05). Pathological damage was also observed in kidneys of LPS-group mice. In Pearson correlation analysis, there was a positive correlation between Ang II and phosphorylated NF-κB-p65 levels, and a negative correlation between Ang II and IκBα levels (p < 0.05). After the application of Ang-(1-7), the levels of urea nitrogen, creatinine, cystatin. c, Ang II, TNFα, IL-1β, IL-6, and mda, as well as the expression of Ang II and phosphorylated NF-κB-p65 in kidneys of LPS + Ang-(1-7)-group mice, were lower than those in kidneys of LPS-group mice, but the levels of sod, TAOC, and IκBα were higher than those of LPS-group mice (p < 0.05). Pathological changes were less severe in mice of the LPS + Ang-(1-7) group. Overall, Ang-(1-7) can decrease the Ang II level, inhibit NF-κB signaling, reduce the inflammatory response, decrease oxidative stress, and mitigate sepsis-associated acute kidney injury.

Highlights

Sepsis-associated acute kidney injury, a condition in which renal function declines rapidly in a short period of time, is characterized by pathophysiological changes that disrupt renal cortex and medullary blood flow and cause tubule necrosis (Alobaidi et al, 2015; Santos et al, 2018)
angiotensin II (Ang II) enzyme-linked immunosorbent assay (ELISA) kit, Ang II polyclonal antibody, TNFα, IL-1β, and IL-6 were purchased from Ray Biotech (Guangzhou, China). rabbit anti-Phospho-NF-κB-p65 (Ser536) and rabbit anti-IκBα were purchased from Cell Signaling Technology (Boston, United Ststes)
No differences were observed in the levels of urea nitrogen, creatinine and cystatin.c between control and Ang-(1-7) groups (p > 0.05)

Summary

Introduction

Sepsis-associated acute kidney injury, a condition in which renal function declines rapidly in a short period of time, is characterized by pathophysiological changes that disrupt renal cortex and medullary blood flow and cause tubule necrosis (Alobaidi et al, 2015; Santos et al, 2018). The mice model of sepsis induced by injection of lipopolysaccharides (LPS) is a common animal model for sepsis research, through which bacterial endotoxin induces animal to produce pathophysiological responses. Nuclear factor-B (NF-κB) is activated by the toll-like receptor 4 (TLR4) on the membrane surface of the target cells, which leads to excessive systemic inflammatory response and oxidative stress. In this way, the physiological action of LPS is achieved (Smith et al, 2015; Mir et al, 2018; Islam et al, 2019; Niu et al, 2019)

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