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
Graphical abstract
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.
References (51)
- et al.
Protective effect of anisodamine in rats with glycerol-induced acute kidney injury
BMC Nephrol.
(2019) - et al.
Agmatine attenuates rhabdomyolysis-induced acute kidney injury in rats in a dose dependent manner
Life Sci.
(2018) - et al.
Underlying mechanisms behind the protective effect of angiotensin (1–7) in experimental rat model of ovarian ischemia reperfusion injury
Life Sci.
(2019) - et al.
The indispensability of heme oxygenase-1 in protecting against acute heme protein-induced toxicity in vivo
Am. J. Pathol.
(2000) - et al.
Toll-like receptor 4: an attractive therapeutic target for acute kidney injury
Lif Sci.
(2021) Multifaceted roles of toll-like receptors in acute kidney injury
Heliyon
(2021)- et al.
Angiotensin-converting enzyme 2 prevents lipopolysaccharide-induced rat acute lung injury via suppressing the ERK1/2 and NF-κB signaling pathways
Sci. Rep.
(2016) - et al.
Exogenous biological renal support improves kidney function in mice with rhabdomyolysis-induced acute kidney injury
Front. Med.
(2021) - et al.
Rhabdomyolysis in COVID-19 patients: a retrospective observational study
Cureus
(2021) - et al.
Acute kidney injury due to rhabdomyolysis
Adv. Med. Biol.
(2018)