Elsevier

Life Sciences

Volume 256, 1 September 2020, 118016
Life Sciences

Curcumin and LOXblock-1 ameliorate ischemia-reperfusion induced inflammation and acute kidney injury by suppressing the semaphorin-plexin pathway.

https://doi.org/10.1016/j.lfs.2020.118016Get rights and content

Abstract

Aims

Ischemia/reperfusion (I/R) is one of the most important causes of acute kidney injury (AKI), a clinical syndrome with kidney dysfunction and high mortality rates. New diagnostic biomarkers need to be defined to better illuminate the pathophysiology of AKI. For the first time, we aim to investigate the protective effects of Curcumin which is known for its antioxidant and anti-inflammatory properties and 12/15 lipoxygenase inhibitor LOXblock-1 on I/R induced AKI by modulating inflammatory processes, oxidative stress, apoptosis and semaphorin-plexin pathway.

Main methods

The rats were divided into five groups, with eight animals per group: Sham, I/R, I/R + DMSO (1%, i.p.), I/R + Curcumin (100 mg/kg, i.p.), I/R + LOXblock-1 (2 μg/kg, i.p.).

Key findings

The renal function biomarkers (BUN, CREA and UA) in serum were significantly increased in the I/R group. The inflammatory (TNF-α, IL-6 and MCP-1), apoptotic (CYCS and CASP3) and oxidative stress parameters (MDA, MPO, TAS and TOS) measured by ELISA were significantly increased in the I/R group. In histopathological analysis, it was observed that I/R caused serious damage to kidney tissue. SEMA3A was found to increase both serum level and mRNA expression in I/R group. It was observed that curcumin and LOXblock-1 reduce inflammatory processes, oxidative stress and apoptosis via the semaphorin-plexin pathway by both measurements and histopathological analysis. Curcumin was proved more effective than LOXblock-1 with its antioxidant feature in I/R injury.

Significance

The current study reveals the protective effects of Curcumin and LOXblock-1 on acute kidney injury by suppressing SEMA3A as a new biomarker.

Introduction

The evaluation of kidney function is important in the treatment of patients with kidney disease or pathologies that affect kidney function. Acute kidney injury (AKI) is a clinical syndrome that results in the failure of urea and other nitrogenous waste products to be excreted from the body due to the sudden loss of function in the kidney, disruption of extracellular fluid volume and electrolyte content [1]. Therefore, the investigation of new diagnostic biomarkers can provide a better understanding of the etiology and pathophysiology of AKI and set goals for future treatments.

The I/R injury is characterized by restriction of blood flow to an organ, followed by restoration and re-oxygenation of the blood flow. The inevitable damage can occur after infarction, sepsis, and organ transplantation, and this phenomenon intensifies tissue damage by initiating an inflammatory cascade, which includes reactive oxygen species (ROS), cytokines, chemokines, and leukocyte activation [2,3]. I/R damage is one of the major causes of AKI [4]. The studies on the treatment and mechanism of kidney injury caused by I/R remain popular in both patients and experimental animals and have not yet been fully elucidated.

Semaphorin (SEMA) and plexins (PLXN) have emerged as central regulators of various physiological and pathophysiological processes in many organs. It was seen that some of the family of semaphorin play an important role both in inflammatory processes that promote tubular damage and in epithelial repair processes necessary for the restoration of kidney function [5]. We aimed to determine whether SEMA3A is an early indicator of AKI, and has the potential to serve as a biomarker in kidney diseases.

The antioxidant properties of Curcumin, a polyphenol compound obtained from Curcuma longa, reduced oxidative stress, tissue destruction, and renal I/R injury [6]. However, the specific mechanisms underlying the protective role of curcumin in I/R-induced AKI are not fully understood. Also, since the effect of Curcumin on the semaphorin-plexin pathway in AKI is not observed in the literature, it is aimed to be investigated for the first time in this study.

Lipoxygenases have important roles in explaining renal inflammation mechanisms. Current studies focus on new lipoxygenase inhibitors. LOXblock-1, one of the 12/15 lipoxygenase inhibitors, has been observed to block 12/15 lipoxygenase, a vehicle of the SEMA3A function, and inhibit SEMA3A-induced damage [7,8].

In the current study, we aim to investigate the protective effects of Curcumin which is known for its antioxidant and anti-inflammatory properties and 12/15 lipoxygenase inhibitor LOXblock-1 on I/R induced AKI by modulating inflammatory processes, oxidative stress, apoptosis and semaphorin-plexin pathway.

Section snippets

Animals and experimental design

This study was approved by the Animal Experiments Ethics Committee of Eskisehir Osmangazi University (Protocol no: 674/2018) and followed the Guide for the Care and Use of Laboratory Animals published by The National Institutes of Health. Forty Wistar albino rats weighing 180–220 g were divided into five groups of eight in each group: Sham (Control), I/R, I/R + DMSO (1%, i.p.), I/R + Curcumin (100 mg/kg, i.p.), I/R + LOXblock-1 (μg/kg, i.p.). The rats were housed in polycarbonate cages (3–4

Curcumin improves more than Loxblock-1 on renal and liver injury biomarkers induced by I/R

As shown in Fig. 1, (a) BUN (b) CREA and (c) UA renal function biomarkers, the serum BUN, CREA and UA levels in the I/R group were found to be statistically higher compared to the sham group (p < 0.001). Curcumin administration reduced BUN and CREA levels compared to I/R group (p < 0.05), but did not change UA levels. LOXblock-1 did not affect renal function biomarkers compared to IR injury.

In the evaluation of electrolyte balance, as seen in Fig. 1(d) Na values increased in the I/R group

Discussion

AKI or renal failure is a rapid dysfunction of the kidney. The serum CREA, BUN and urine output used in the diagnosis of AKI are late and non-sensitive markers [13]. Therefore, we aimed to investigate new diagnostic biomarkers in AKI. The I/R injury is one of the major causes of acute kidney failure [14]. The studies on the treatment and mechanism of kidney injury caused by I/R remain popular. Animal models are widely used to understand the mechanisms of I/R. It is noted that I/R causes serious

Conclusions

In pre-clinical rat models, we show that the semaphorin-plexin pathway represents a new and promising pharmacological target in kidney diseases and that in the future these findings will have to be clarified. The effect of curcumin on acute kidney injury was associated with the semaphorin-plexin system. Antioxidant feature of curcumin has come to the fore compared to LOXblock-1. Better understanding of 12/15 LOX enzyme inhibitors and semaphorins in different kidney pathologies will lead to new

Acknowledgments

This study was supported by the Commission of Scientific Research Projects of Eskişehir Osmangazi University, Eskisehir, Turkey with the grant numbers: 2019-2344 and 2019-1915.

Declaration of competing interest

Authors declared that there is no conflict of interest.

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