Elsevier

Life Sciences

Volume 303, 15 August 2022, 120678
Life Sciences

Angiotensin 1–7 mitigates rhabdomyolysis induced renal injury in rats via modulation of TLR-4/NF-kB/iNOS and Nrf-2/heme‑oxygenase-1 signaling pathways

https://doi.org/10.1016/j.lfs.2022.120678Get rights and content

Highlights

  • RM induced kidney injury may be linked to the depletion of the ACE-2 and Ang1–7.

  • The ACE-2/Ang1–7/MasR axis may serve as a novel therapeutic option in RM-induced AKI.

  • TLR-4/NF-kB/iNOS pathway may be involved in the renoprotective effect of Ang1–7.

Abstract

Aims

Rhabdomyolysis (RM) is a critical condition with a high mortality rate, but effective management is still deficient. Till date, there are no studies that have addressed the effect of angiotensin 1–7 in this condition, hence, the rationale of this study was to evaluate the potential protective effect of Angiotensin 1–7 (Ang1–7), on rhabdomyolysis (RM) induced kidney injury in rats and detecting the underlying mechanistic insights.

Main methods

Forty adult male albino rats were divided into groups; the control group, RM group, RM+Ang1-7 group, and RM+Ang1-7+ A779 group. Sera and urine samples were collected for analysis of renal and muscle injury markers. Kidney tissues were taken for estimation of oxidative, inflammatory, and apoptotic markers as well as angiotensin-II (Ang II) and Ang1–7. Renal histology and expression of inducible nitric oxide synthase-1 (iNOS), real-time PCR for angiotensin-converting enzyme-2 (ACE-2), nuclear erythroid factor-2 (Nrf-2), Toll like receptor 4 (TLR-4) and NF-kB in kidney tissues were also measured.

Key findings

Induction of RM caused renal oxidative stress injury, inflammation, apoptosis and marked deterioration in kidney functions as well as reduction of Ang1–7 and raised Angiotensin-II level in kidney tissues. Administration of Ang1–7 to the RM group reversed all the affected parameters which were blocked by A779 administration (Mas receptor blocker).

Significance

We concluded that Ang1–7 could be a potential therapeutic agent that could mitigate RM-induced renal injury. The underlying mechanisms may involve Stimulation of the ACE-2/Ang1–7/MasR axis and modulation of TLR-4/NF-kB/iNOS and Nrf-2/heme‑oxygenase -1 pathways.

Introduction

Rhabdomyolysis (RM) is a critical clinical condition with a worldwide high mortality rate, it is a sequale of acute disruption of skeletal muscle that results from various etiologies such as crush syndrome, myopathies, toxins, and recently it was reported in COVID-19 patients [1], [2]. Acute kidney injury (AKI) is a prominent complication that occurs in nearly 13%-50% of patients that had RM which in turn leads to rapid deleterious effects on renal functions and acute renal failure and other serious complications such as disseminated intravascular coagulopathy and acute compartment syndrome [3]. Nowadays, searching for effective therapies to prevent and cure RM-induced AKI has attracted more attention, particularly with the notion that it is a feature present in some COVID-19 patients, although till now, there is no established therapy to endorse recovery [4].

The renin-angiotensin system (RAS) plays a pivotal role in the development and progression of kidney diseases. Thus, blockade of RAS using angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers, can efficiently defeat the progression of kidney diseases in both animal experiments and clinical studies [5]. The ACE-2/Ang1–7/Mas receptor axis plays a counter-regulatory role to the ACE/Ang II/Ang II type 1 receptor (AT1R) axis of the RAS, and its activation has been shown to exert a renoprotective effect in kidney diseases [6]. Other studies have shown that the removal or inhibition of the ACE-2 leads to exacerbating kidney diseases [7].

The renoprotective effects of Ang1–7 are well documented [8]. In previous studies on some renal injury models such as diabetic nephropathy and obstructive nephropathy, Ang-1-7 showed anti-inflammatory, antioxidant, and anti-fibrotic effects [9], [10]. However, to date, the impact of Ang1–7 on RM-induced kidney injury has not been evaluated. In the light of the role of Mas receptor in the RAS, it is supposed that Ang1–7 could protect the kidney against RM-induced kidney damage. Therefore, this research was conducted to investigate the possible effects of the Mas receptor agonist; Ang1–7, and its antagonist; A779 on RM-induced renal injury in rats and explore the underlying mechanistic insights that could be involved.

Section snippets

Animals and ethical issues

Forty adult male albino rats (Sprague Dawley strain), weighing 200–250 g were included in the current study. Rats were purchased from the National Research Centre, Cairo, Egypt. They were housed in groups in separate cages at room temperature with natural dark/light cycles, they were fed a standard commercial rat chow (Nile Company, Egypt) and tap water ad libitum for 2 weeks before starting this study. The protocol was ethically approved by The Laboratory Animals Maintenance and Usage

Changes in serum level of muscle injury biomarkers in different groups

Both creatine kinase MM (CK-MM) and lactate dehydrogenase (LDH) serum levels were significantly increased in rats subjected to RM when compared to the control group, treatment with Ang1–7 significantly decreased the enzymes level, but still significant from control levels, while administration of A779 blocked the effect of Ang-1-7 and the level of both enzymes was still significantly elevated (Fig. 1).

Changes in renal function and injury biomarkers in different groups

As shown in Table 2, serum levels of urea, creatinine, Kim-1 and cystatin c, and urinary

Discussion

Rhabdomyolysis-induced acute renal injury is a pathophysiological process in which multiple intermingled mechanisms are involved. Most studies used the intramuscular injection of 50% glycerol (10 mL/kg) in the hind limbs of rats as an experimental model because this dose of glycerol is non-lethal in most rats [12]. Glycerol injection into the muscle causes its damage with consequent release of myoglobin and muscle enzymes into the circulation, that filtered through the glomeruli resulting in

Conclusions

Ang1–7 proved to be protective on kidneys subjected to RM via restoration of the normal balance of the RAS system, suppression of inflammation, oxidative stress and apoptosis. The underlying mechanisms may involve down-regulation of TLR-4/NF-kB/iNOS and up-regulation of Nrf-2/heme‑oxygenase-1 pathways. Hence, Ang1–7 could be a potential therapeutic agent in the management of RM-induced acute renal injury.

Recommendations

To the best of our knowledge this is the first study that have addressed the impact of Ang1–7 on RM induced acute renal injury in rats and thus provides a base for further future experiments to examine its specific molecular mechanisms which need more clarification. Besides, its effect on humans should be evaluated.

Author contribution to study

All authors declare that all data were generated in-house and no paper mill was used.

Dr. Elshymaa and Dr. Heba chose the research design, performed the experimental part and wrote the manuscript. Dr. Sara accomplished and wrote the histopathology, immunohistochemistry sections and revised the manuscript. Dr. Bothina performed and wrote the RT-PCR analysis. All authors revised the final version of the manuscript and agreed for its publication.

Funding sources

This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

Declaration of competing interest

All authors declare that they have no conflict of interest.

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