Salusin-β mediates tubular cell apoptosis in acute kidney injury: Involvement of the PKC/ROS signaling pathway

Qing-Bo Lu,Qiong Du,Hui-Ping Wang,Zi-Han Tang,Yuan-Ben Wang,Hai-Jian Sun

doi:10.1016/j.redox.2019.101411

Abstract

Salusin-β is abundantly expressed in many organs and tissues including heart, blood vessels, brain and kidneys. Recent studies have identified salusin-β as a bioactive peptide that contributes to various diseases, such as atherosclerosis, hypertension, diabetes and metabolic syndrome. However, the role of salusin-β in the pathogenesis of acute kidney injury (AKI) is largely unclear. In the present study, we investigated the roles of salusin-β in cisplatin or lipopolysaccharide (LPS)-induced renal injury. Herein, we found that salusin-β expression was upregulated in both renal tubular cells and kidney tissues induced by both cisplatin and LPS. In vitro, silencing of salusin-β diminished, whereas overexpression of salusin-β exaggerated the increased PKC phosphorylation, oxidative stress, histone γH2AX expression, p53 activation and apoptosis in either cisplatin or LPS-challenged renal tubular cells. More importantly, salusin-β overexpression-induced tubular cell apoptosis were abolished by using the PKC inhibitor Go 6976, reactive oxygen species (ROS) scavenger NAC, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin (Apo) or p53 inhibitor Pifithrin-α. In animals, blockade of salusin-β alleviated PKC phosphorylation, ROS accumulation, DNA damage, and p53 activation as well as renal dysfunction in mice after administration of cisplatin or LPS. Taken together, these results suggest that overexpressed salusin-β is deleterious in AKI by activation of the PKC/ROS signaling pathway, thereby priming renal tubular cells for apoptosis and death.

Highlights

Acute kidney injury (AKI) is manifested by a sharp decline in renal function that threats millions of patients with high mortality and morbidity [1]
Both protein level and mRNA expressions of salusin-β are elevated in the kidney of cisplatininduced mice (Fig. 1E and F), which was paralleled by a drastic increase in renal and plasma salusin-β level of cisplatin-treated mice (Fig. 1G and H)
We investigated whether salusin-β mediated acute renal dysfunction induced by cisplatin or LPS, as well as the underlying mechanisms

Summary

Introduction

Acute kidney injury (AKI) is manifested by a sharp decline in renal function that threats millions of patients with high mortality and morbidity [1]. It is believed that several factors are involved in the pathogenesis of AKI, including renal venous congestion, inflammatory response, oxidative stress, coagulation cascade activation, renal hypoperfusion and microcirculatory disturbance [2,3,4]. The underlying mechanisms of cisplatin-induced AKI are very complicated, but massive renal proximal tubular cell death, including cell necrosis and apoptosis, nuclear DNA injury, oxidative stress inflammatory response and activation of apoptotic cascades are involved [10,11]. As an important component of cell wall of most Gramnegative bacteria, lipopolysaccharide (LPS) is able to mimic sepsis-related AKI in animals via triggering enormous cytokine synthesis, excessive oxidative stress, renal hypoperfusion, which eventually leads to a rapid decline in renal function [13]. In this study, both cisplatin and LPS were used to establish two rodent models of AKI

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Results

Conclusion