Review Article Plants with Therapeutic Potential for Ischemic Acute Kidney Injury: A Systematic Review
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Hindawi
Evidence-Based Complementary and Alternative Medicine
Volume 2022, Article ID 6807700, 22 pages
https://doi.org/10.1155/2022/6807700
Review Article
Plants with Therapeutic Potential for Ischemic Acute Kidney
Injury: A Systematic Review
Arif Ali ,1 Tiago Lima Sampaio ,2 Haroon Khan ,3 Philippe Jeandet ,4
Esra Küpeli Akkol ,5 Humaira Bahadar ,6 and Alice Maria Costa Martins 2
1
Postgraduation Program in Pharmacology, Federal University of Ceará, Fortaleza, Brazil
2
Department of Clinical and Toxicological Analysis, Federal University of Ceará, Fortaleza, Brazil
3
Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan
4
University of Reims Champagne-Ardenne, Research Unit Induced Resistance and Plant Bioprotection, USC INRAe 1488,
SFR Condorcet FR CNRS 3417, Faculty of Sciences, Reims 51687, France
5
Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, Etiler, Ankara 06330, Turkey
6
Department of Biochemistry and Molecular Biology, Federal University of Ceará, Fortaleza, Brazil
Correspondence should be addressed to Haroon Khan; haroonkhan@awkum.edu.pk and Esra Küpeli Akkol; esrak@gazi.edu.tr
Received 4 February 2022; Accepted 30 March 2022; Published 23 May 2022
Academic Editor: Antonietta Rossi
Copyright © 2022 Arif Ali et al. This is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Acute kidney injury (AKI) is a complex condition which has an intricate pathology mostly involving hemodynamic, in-
flammatory, and direct toxic effects at the cellular level with high morbidity and mortality ratios. Renal ischemic reperfusion
injury (RIRI) is the main factor responsible for AKI, most often observed in different types of shock, kidney transplantation, sepsis,
and postoperative procedures. The RIRI-induced AKI is accompanied by increased reactive oxygen species generation together
with the activation of various inflammatory pathways. In this context, plant-derived medicines have shown encouraging
nephroprotective properties. Evidence provided in this systemic review leads to the conclusion that plant-derived extracts and
compounds exhibit nephroprotective action against renal ischemic reperfusion induced-AKI by increasing endogenous anti-
oxidants and decreasing anti-inflammatory cytokines. However, there is no defined biomarker or target which can be used for
treating AKI completely. These plant-derived extracts and compounds are only tested in selected transgenic animal models. To
develop the results obtained into a therapeutic entity, one should apply them in proper vertebrate multitransgenic animal models
prior to further validation in humans.
1. Introduction of AKI has almost doubled in number over the past two
decades [3, 4]. The inpatients are more likely to suffer from
Acute kidney injury (AKI) is a widely spread and pro- AKI as a result of secondary disease complications or due to
spectively life-taking disease. Presently, AKI definition is an adverse reaction to therapy. The prevalence of AKI
based on the decline in the kidney function in more or less among seriously ill patients is 25–67%, while the mortality
than a week [1]. Based on AKI genesis, this disease has been ratio is 30–60% even if the severity of the disease subsides
characterized into three categories, prerenal—a physiologic [5–8].
reaction of the normal structural kidney towards hypo- Annually, about 2100 per million of the population suffer
perfusion; intrinsic or intrarenal—injury to the kidney pa- from AKI. In developed countries, the cases of AKI are
renchymal cells; and postrenal—a response towards expected to be more than 2 million per annum. Among
a urinary tract obstruction [2]. The impact of AKI in long these, 1.5 million patients survive of which many patients
run on public health is enormous. AKI is associated with progress to advanced stages of chronic kidney disease (CKD)
increased number of morbidity and mortality. The incidence within a period of 24 months. To these numbers, one can add2 Evidence-Based Complementary and Alternative Medicine
over 300,000 patients to the category of advanced stage of reperfusion in rats,” “renal ischemia reperfusion,” “renal
CKD per year. The episodes of AKI in CKD patients lead to ischemic reperfusion and plant extracts,” “nephroprotection
upsurge in the development of end-stage renal disease against renal/kidney with renal. reperfusion,” and “plant
(ESRD). These figures provide the fact that the major at- extracts against kidney ischemia reperfusion.” Articles
tributable risk in patients suffering from CKD is AKI [1]. published from 2000 to 2019 were selected to write this
AKI is a multifactorial condition, and the pathogenesis review.
of which is based on hemodynamic, inflammatory, and After careful reading of the articles, the central in-
direct toxic effects at the cellular level [9]. However, renal formation was critically collected and discussed according to
ischemic reperfusion injury (RIRI) is being considered as the following thematic sessions: kidney with renal. reper-
one of the foremost reasons of AKI which is accompanied by fusion injury, epidemiology, etiology of AKI, diagnosis,
50% mortality ratio in intensive care units [10–12]. Renal treatment of AKI, mechanisms by which plants ameliorated
ischemic reperfusion injury may occur due to various rea- renal I/R injury induced-AKI, and effects on biomarkers and
sons such as administration of vasoconstrictive drugs or renal tissues. The final curatorship of the articles took place
radio-contrast agents. Hypotension also leads to RIRI which through the tabulation of relevant information such as
more commonly occurs in sepsis or when a large volume of substances, sources, experimental models, methodological
fluid is lost in trauma. Similarly, it can be initiated by various aspects, mechanisms, and effects.
clinical ailments like myocardial infarction, different types of
strokes, or due to postsurgical operations such as organ 3. Results
transplant, cardiac surgery, extracorporeal lithotripsy, and
adrenal aneurysm. In case of trauma or shock, the body 3.1. Renal Ischemic Reperfusion Injury. Ischemic reperfusion
compensates fluid losses by various mechanisms, but due to (I/R) injury is a pathophysiological condition which is
unmet need of high oxygen demand of cells and insufficient generated by preliminary impediment of blood flow to an
metabolic substrate availability, the cellular injury often organ followed by restoration or reperfusion. The duration
leads to organ failure [13–15]. and extent of ischemia govern the range of cell death or loss
Literature data prove the hypothesis that acute kidney of organ function. The reperfusion phase is thought to re-
injury due to ischemic reperfusion is associated with changes instate oxygen and nutrient requirement of an organ though
in hemodynamics and dysfunction of endothelial cells be- it also synergizes the oxidation and inflammatory stress both
cause of a high level of reactive oxygen species (ROS) and locally and systemically resulting in cell damage. This whole
reactive nitrogen species (RNS) leading to decreased pro- process is being entitled as I/R injury [18].
duction of nitrogen oxide and intracellular energy store Renal I/R injury causes hypoxia as a result of which
exhaustion. Both ROS and RNS stresses cause lipid per- metabolism is altered leading to depletion of adenosine
oxidation, oxidative DNA damage, modification of in- triphosphate (ATP) and increase in lactate concentration.
flammatory pathways, modification of leukocyte function, This provokes an electrolyte imbalance such as an increased
and microvascular reduction in blood flow to renal medulla sodium level as well as a water influx and an intracellular
because of vascular congestion [10]. Similarly, Malek and calcium overload. As a result, an increase in apoptosis be-
Nematbakhsh have mentioned that ROS is involved in sides cell necrosis and intracellular acidosis is observed.
kidney injury by lipid peroxidation, while oxidative damage Furthermore, reperfusion leads to generation of ROS de-
of proteins and DNA contributes to apoptosis and cell creasing SOD and catalase as well as GPx levels. Reperfusion
necrosis. Downregulation of antioxidant enzymes such as inhibits the cytochrome c oxidase and increases NO levels.
catalase, superoxide dismutase (SOD), and glutathione These parameters are responsible for protein and lipid
peroxidase (GPx) might be responsible for the pathophys- peroxidation (which increases MDA levels) along with DNA
iology of the ischemic reperfusion injury [16]. damage, which further aggravates cell necrosis and apoptosis
The most efficient and effective ways to prevent ischemic [19, 20]. Because of the redox imbalance, a local and systemic
reperfusion (I/R) injury is thus to scavenge these ROS and inflammatory process is activated. I/R injury is also re-
free radicals. According to current scientific data, traditional sponsible for the initiation of several inflammatory reactions
natural medicines have been found very effective against within the renal parenchyma. In addition to infiltration of
ROS and oxidative stress. Moreover, natural therapies and neutrophils, renal I/R injury is accountable for the gener-
mixtures have been shown to be very efficacious in various ation of many inflammatory cytokines, for instance IL-6, IL-
inflammatory conditions [17]. The purpose of this review is 1, and TNF-α [21].
to summarize the treatments used for AKI induced by I/R In experimental renal I/R injury models, the renal blood
injury via plant extracts and plant-derived natural com- flow is completely blocked by clamping the renal artery. This
pounds, thereby offering some clue for further in-depth blocking phase is called ischemia, the duration of which is
research. usually from 20 to 60 minutes, and this phase is accom-
panied by hypoxia in addition to loss of the GFR function.
2. Materials and Methods Within the first 30 minutes of ischemia, the injury is still
limited, but within 45 minutes, the injury becomes more
Relevant articles were retrieved from various database search regular and confluent with different levels of necrotic le-
engines such as Google Scholar, PubMed, and ScienceDirect sions. After 60 minutes, necrotic cells become infarcted
by typing key terms “acute kidney injury,” “renal ischemic [22–25]. A total blockage during ischemia results intoEvidence-Based Complementary and Alternative Medicine 3
endothelial cell injury with functional loss. It also results in AKI commonly occurs in hospitalized patients and more
substantial modifications of the transcription program of frequently in those who are admitted in ICU [39, 42]. The
vasoactive cytokines and leukocyte function [26]. Different prevalence of AKI in ICU admitted patients is mentioned in
approaches are in practice for the induction of renal is- various epidemiological studies in accordance with KDIGO
chemia in experimental models, such as the simultaneous criteria [39, 43, 44]. A study performed by Kaddourah et al.
application of bilateral renal ischemia [27, 28], while others included children and young adults having an age range
apply unilateral ischemia in one kidney and perform ne- from 3 months to 25 years. The total number of patients
phrectomy of the other [29, 30]. registered were 4683, admitted in 32 ICUs. During the first
Removal of clamps and restoration of blood supply and week of admission at the hospital, the reported AKI in-
nutrients is called reperfusion. This rapid resupply of blood cidence was 27%, of whom 12% developed severe AKI [45].
is essential for the survival of cells, which are being damaged The ratio of AKI in hospitalized pediatric patients is
by ischemia. However, reperfusion, which is accompanied about 5%, while in seriously ill pediatric patients, it ranges
by a return of oxygen, itself is the major step responsible for between 20 and 70% accompanied by high morbidity and
further cell injury [20]. The foremost damaging effect of mortality rates [46, 47]. A systematic review based on 312
reperfusion is the generation of ROS via mitochondria, cohort studies from high-income developed countries
which are responsible for acute injury to cells, persisting for comprising 49 million patients of AKI has shown that one in
weeks without any intervention. ROS causes a disturbance in five adults suffered from AKI. Likewise, one in three children
adenosine triphosphate (ATP) production and calcium were displaying AKI. Another cohort study (n � 5, 23,390)
regulation leading to mitochondrial permeability transition performed in Scotland and based on the RIFLE classification
pore (MPTP) opening. This dysregulation initiates cell ne- system reported that the incidence of AKI was 1,811 per
crosis and apoptosis as well as cell death [31]. million residents [48]. The prevalence of AKI was also
Various sources have been linked with ROS generation studied in 120,123 patients from January 2000 to December
following I/R injury such as enzymatic sources including 2005 in 57 ICUs across Australia [49], the number of AKI
xanthine oxidase, NADPH oxidase, the mitochondrial elec- cases mentioned being 36%. According to the RIFLE clas-
tron transport chain, and nitric oxide synthase [32]. The ROS sification of AKI, most of the cases (16%) belonged to the “R”
generated from these sources by I/R injury highly target category (stage I injury), 13.6% were of “I” (stage II injury),
proteins, cell membrane lipids, and nucleic acids [33]. Besides and 6.3% cases were related to the “F” category (stage III
the direct cytotoxic effect of renal I/R injury, ROS also prompts injury). The AKI was associated with an increased mortality
an inflammatory response in renal endothelial and paren- ratio [49]. Concerning AKI prevalence in ICUs, a study was
chymal cells. As a result, many proinflammatory cytokines conducted in Thailand including 5,377 patients from Feb-
such as the tissue necrosis factor-α (TNF-α), interleukins (IL) ruary 2013 till July 2015. Among them, 2471 (53%) patients
1, IL-6, and many chemokines like the monocyte chemo- were diagnosed with AKI during hospital admission [50].
attractant protein (MCP) and IL8 are released. The ROS and Another study from Scotland has shown a prevalence of 2147
cytokines generated as a result of kidney injury induce an AKI cases per one million residents [48]. Most of the
upsurge in the expression of adhesion biomarkers, for instance, aforementioned studies have thus reported a sovereign link
the intercellular adhesion molecule (ICAM), the vascular cell of AKI with a greater risk of mortality. The worldwide
adhesion molecule (VCAM), and the P-selectin [21, 34]. As- projected mortality rate of AKI is 24% in the adult pop-
sembling of cytokines, chemokines, ROS, and adhesion ulation and 13.8% in children. Among aged population, the
molecules further aggravate the renal injury. risk of mortality from AKI is even higher [51].
3.2. Clinical Presentation of AKI 3.2.2. Etiology of AKI. There is a difference in the suscep-
tibility of each individual to develop AKI caused by exposure
3.2.1. Epidemiology. Accurate elucidation of AKI epidemi- to numerous factors depending, for instance, on the dura-
ology is modulated by many factors such as various defi- tion of the exposure, its type, heterogeneity, and severity
nition of AKI and variations in case mingling. For instance, [52]. As stated before, AKI is more common in critically ill
patients of non-ICU cases are different from ICU patients. patients and its cause is frequently multifactorial. Sepsis is
Similarly, there is a difference between cases in general one of the serious conditions that is increasing in hospi-
hospital ICU compared to rural hospital ICU; postoperative talized patients. For example, a 22-year analysis of hospi-
cardiac patients are different from those displaying liver talized patients carried out in the U.S has revealed a yearly
cirrhosis [35]. Many factors are involved in the variation of growth of 8.7% in sepsis diagnosis [53]. Sepsis has been
AKI figures, in developed as well as in developing countries found as the foremost cause of AKI accounting for 45 to 70%
[36]. Aged populations are more affected by AKI in de- of the cases of AKI being linked to sepsis. A large prospective
veloped countries [37], while in developing countries, observational study performed by Bagshaw et al. has
mostly adults and children suffer from AKI due to socio- mentioned that, among 29,000 patients, 5.7% developed AKI
economic and environmental influences [38]. Studies in- of which 47.5% cases were due to sepsis [54]. Likewise,
volving adult population have revealed that AKI is pediatric studies showed that sepsis was the major risk factor
accompanied by an increased rate of mortality, hospital ICU in 18 to 58% of the patients acquiring AKI [55].
stay, and dependency on mechanical ventilation [39–41].4 Evidence-Based Complementary and Alternative Medicine
Major surgery is another factor leading to AKI, as biomarkers which may characterize AKI in its earlier stages
revealed by Grams et al. (2016) according to a large cohort [66, 67]. For the subclinical diagnosis of AKI, two types of
study involving 161,185 participants. Among the partici- novel biomarkers known as damage and stress biomarkers
pants, 11.8% suffered from AKI after a major surgery, are used. The novel damage biomarkers are the neutrophil
though other risk factors in these patients were old age, male gelatinase-associated lipocalin (NGAL) and the kidney in-
gender, overweight, and African American race. There were jury molecule 1 (KIM-1), whereas the insulin-like growth
differences in the prevalence of AKI with respect to the type factor binding protein 7 (IGFBP-7) and tissue inhibitor of
of surgery, but the most affected ones were patients with metalloproteinase-2 (TIMP-2) belong to the novel stress
cardiac surgery [56]. biomarkers. These biomarkers may predict the detection of
Another major cause of AKI is cardiogenic shock, an AKI, but their clinical application is still uncertain [68, 69]. A
ailment characterized by insufficient cardiac output causing combo of urinary TIMP-2 and IGFBP-7 called as nephron-
low blood pressure with symptoms of end organ hypo- check has been recognized by the FDA for the diagnosis of
perfusion such as oliguria [57]. A study performed by Van AKI [70]. Other tools that are used for AKI diagnosis are
den Akker et al. mentioned that, out of 39 cardiogenic shock clinical imaging techniques involving ultrasonography,
patients admitted in ICU, 24 developed AKI within the first contrast-enhanced ultrasonography, computerized tomog-
48 hours of their admission [58]. The prevalence of AKI in raphy, conventional B-mode imaging, and magnetic reso-
cardiogenic shock patients is very frequent and associated nance imaging [66]. AKI is a severe disease, progressive in
with high mortality during the first 90 days of cardiogenic nature, meaning that continued insult will lead to increased
shock [57]. Burns can likewise lead to AKI with a very high injury and loss of organ function with serious consequences
incidence rate of 30% and with 80% mortality. A large such as death. Timely diagnosis of AKI will lead the clinician
amount of fluids loss from a burn injury causes hypovolemia to intervene and make a proper treatment plan [71].
and a substantial decline in cardiac output resulting in
decreased renal flow and leading to ischemia and cellular
death. The ischemia further aggravates free radical forma- 3.2.4. Treatment of AKI Using Drugs and Plant-Based
tion and cellular structure damage ultimately causing ad- Therapies. Treatment and management plans for AKI are
ditional kidney injury [59]. Drugs are notorious for causing based on its causative agent. Those patients in whom AKI is
nephrotoxicity with 20 to 40% AKI cases due to medications, not developed but display a risk factor or been exposed to
this ratio reaching 60% among the elderly population. a risk factor must undertake clinical assessment and in-
Aminoglycosides and other antimicrobials (antivirals and vestigation [72]. As AKI is a multifactorial and heteroge-
antifungals) are the most common drug classes responsible neous disease often accompanied by comorbidities, and
for AKI [60]. Other potential classes of drugs include identification of an appropriate pharmacological approach,
nonsteroidal anti-inflammatory drugs (NSAID’s), angio- which can assist in full cure, is quite challenging. Moreover,
tensin-converting enzyme inhibitors (ACE), and calcineurin at the time of the diagnosis, the disease is almost established
inhibitors. In case of appearance of any AKI symptoms in in most of the cases. AKI patients frequently suffer from
patients during therapy, drug administration should be increased potassium levels, metabolic acidosis, fluid over-
stopped [61]. Besides, numerous infectious diseases are load, or increased level of blood urea due to decreased GFR.
responsible for AKI such as malaria, leptospirosis, dengue, The pharmacological therapy is commonly based on treating
yellow fever, and scrub typhus. Similarly, animal venoms these symptoms rather than the disease itself [73].
such as snakes and various arthropods also cause AKI [62]. Various drug classes are used for the treatment of AKI
according to its triggering factors. For instance, vasopres-
sors, diuretics, as well as intravenous (I/V) fluids are ad-
3.2.3. Diagnosis. The diagnosis of AKI has been evolved over ministered for management of the oliguria which is related
the time. Conventionally, AKI diagnosis is based on the with decreased GFR in addition to an increase in salt and
measurement of serum creatinine (SCr) and the reduction in water retention. The purpose of this therapy is to resume
urine yield. The definition of AKI by Acute Dialysis Quality a normal cardiac output, a systemic hypotension, and
Initiative (ADQI) group based on Risk, Injury, Failure, Loss, a neuroendocrine response. However, as observed in many
End-stage (RIFLE) criteria has been modified by the AKI- studies, this therapy leads to shoddier organ function loss
network (AKIN) with slight amendments [63, 64]. These two with worse consequences in routine surgery cases. Main-
definitions and classification benchmarks of AKI were taining this therapy for a long time is also challenging and
merged in 2012, and consequently, Kidney Disease Im- leads to many adverse responses such as interstitial edema
proving Global Outcomes (KDIGO) criteria came into ex- and organ dysfunction [74].
istence. In view of the KDIGO criteria, AKI is diagnosed if Loop diuretics are being used based on a well-known
SCr ≥0.3 mg/dl within 48 hours or escalating by 1.5 times notion that it transforms oliguric AKI patients into non-
from the baseline level within a week or less. AKI stages were oliguric ones providing an electrolyte balance [75]. Re-
classified by determining changes in SCr or urine output gardless of its extensive prescription in AKI patients,
[65]. improvement of the clinical picture is still missing. More-
Current criteria of AKI diagnosis are widely used and over, some data suggest more damage compared to benefits
accepted but have, regrettably, limitations. Both SCr and in selected cases [76]. The results of the study carried out by
urine output are imperfect biomarkers as compared to other Mehta et al. have shown that diuretic administration inEvidence-Based Complementary and Alternative Medicine 5
critically ill patients suffering from kidney diseases is ac- modern pharmaceutical industry is also capitalizing in re-
companied with increased rate of mortality and irreversible search based on new chemical entities (NCEs) from me-
renal function loss [77]. A meta-analysis by Ho and Power dicinal plants. Currently, among the approved NCEs from
has mentioned that furosemide, a loop diuretic, when used natural sources, 25% are derived from plants. Moreover, in
in AKI patients, has no impact on mortality ratio and risk of some therapeutic areas such as oncology, there are 60%
renal replacement therapy (RRT) reduction [78]. approved plant-derived medicines [92–94]. According to the
Among the renal vasodilators, dopamine has shown World Health Organization (WHO), 65–80% population are
inability to protect or change the progression of ischemic using plant-derived medicines in developing countries [95].
AKI. Likewise, fenoldopam induces a dose-dependent hy- As stated previously, oxidative and inflammatory
potension which may aggravate AKI. However, according to stresses are the main factors contributing to the patho-
another review based on 13 studies regarding fenoldopam physiology of I/R injury [96–99]. In this context, easy
role in patients enduring cardiovascular surgery, it was availability and accessibility to plant-derived therapies are of
reported that it may decrease the RRT and in-hospital prime importance. Plants represent a rich source of phy-
mortality rate [79]. Another pharmacological intervention in tochemicals which have a high potential to act both as
AKI is statin therapy. A meta-analysis by He et al. showed exogenous antioxidant and anti-inflammatory agents, as
that pretreatment and posttreatment with statins in patients evidenced by many studies [27, 100–104]. Therefore, treating
undergoing cardiac surgery increases the risk of cardiac I/R-induced AKI with plant-derived extracts and com-
surgery associated with AKI, the risk being higher with pounds is the most practical approach. The aim of this
rosuvastatin compared to atorvastatin [80]. Many drugs review is to enlist such plant-based therapies which are
display encouraging effects in specific stages of AKI, but tested in experimental models of renal I/R injury, thus
none of them have shown any assured evidence in the providing an insight for future research.
protection of AKI. Many factors may be responsible for such Plant-based therapies provide nephroprotection against I/
a failure, e.g., most pharmacological therapies are targeting R-induced AKI mainly by increasing the levels of antioxidant
only a single pathway. Similarly, there is vagueness on enzymes such as superoxide dismutase (SOD) and catalase as
initiation, discontinuation, and exact dosing for a given well as glutathione levels, thereby producing antioxidant effects
pharmacological therapy [81]. Obstacles in clinical trials is against ROS [105–108]. Similarly, they provide an anti-in-
another accountable factor, for instance, secondary diseases flammatory effect mostly by inhibiting inflammatory cytokines
in enrolled patients for clinical trials are mainly responsible like the tissue necrosis factor alpha (TNF-α), interleukin 1β (IL-
for increased mortality ratio. Likewise, lack of agreement on 1β), and interleukin-10 (IL-10) [100, 109, 110].
a common definition of AKI, and its complex etiology are The nephroprotective role provided by various plants
additional factors responsible for insufficient pharmaco- against I/R injury can be attributed to their rich contents in
logical options to treat this ailment [82]. phytochemicals such as flavonoids, phenols, polyphenolics,
With the expansion of research, new cellular and sub- alkaloids, tannins, terpenes, and saponins. Many plants
cellular information has become available regarding the contain more than one of these highly antioxidant and anti-
pathophysiology of AKI. As a result, more emphasis has inflammatory compounds. A summary of the various effects
been laid on inflammation, oxidative stress, and immune of plants against I/R induced-AKI is presented in Table 1.
response modulation [83]. One essential condition of AKI is
a kidney I/R injury, which is accompanied by inflammatory
responses such as macrophage and neutrophil infiltration. 4. Mechanisms by Which Plants Ameliorated
Similarly, mitochondria are also affected due to ROS gen- Renal I/R Injury-Induced AKI
eration, causing changes both at cellular and vascular levels
[27, 84]. Renal I/R injury leads to the reduction of anti- 4.1. Increasing Antioxidant Levels. Plant-derived extracts
oxidant molecules such as glutathione and an increase in and natural compounds ameliorated kidney I/R injury-in-
lipid peroxidation which can be identified by an enhanced duced AKI by increasing the levels of antioxidant enzymes
level of malondialdehyde [84]. The generation of ROS, in- and antioxidants (Table 1). These enzymes include super-
flammatory molecules, and activation of apoptotic pathways oxide dismutase (SOD), catalase, and glutathione peroxidase
and the caspase pathway leads to renal cytotoxicity and (GPx). The SOD provides natural defense against oxidative
initiate a vicious circle of cell injury [85]. stress as it converts O2 into H2O2 (equation (1)). H2O2 does
Another emerging pharmacological therapy is the use of not contain any unpaired electrons and as such is not a free
plant-derived extracts and natural compounds with anti- chemical radical. However, H2O2 can penetrate easily into
oxidant and anti-inflammatory properties. Moreover, these cells and act as a poor oxidizing agent. The catalase and GPx
latter ones act via multiple mechanisms to protect cell injury then detoxify H2O2 into H2O, O2, and H2O, respectively
from ROS and inflammatory cytokines [86]. Since ancient (equation (2) and (3)) [165, 166].
times, many plants are used for treatment purposes and are
still in practice all over the world [87, 88]. The use of me- 2O−2 + 2H ⟶ SOD H2 O2 + O2 , (1)
dicinal plants for treatment purposes is based on hundred-
year-old beliefs and innumerable experiences [89–91]. 1
2H2 O2 ⟶ catalase 2H2 O + O2 , (2)
There is a growing interest in developing medicinal plant- 2
derived products as treatments all over the world. The6
Table 1: Plant-derived extracts and compounds having nephroprotective effects against renal ischemic reperfusion injury-induced acute kidney injury.
Route of
Substance used Source Experimental model Ischemia Mechanism Administration and Effects Reference
order
↓Urine osmolality
↓SCr, urea, uric acid, MDA
↓FENa+, FEK+, FECl-
↓uKim-1,
Male Wistar albino rat (in Right renal nephrectomy and left kidney ↓Proteinuria, Albuminuria
Matricaria chamomilla, M. crassifolium, Oral route
vivo) LLC-MK 2 cells (in ischemia for 60 min followed by 48 h Antioxidant, anti-inflammatory, antiapoptotic ↓Renal histopathological [26]
Salvia runcinata, Vanillosmopsis sp. posttreatment
vitro) reperfusion score
↑Creatinine clearance, GSH
(−)-α-Bisabolol ↑Water consumption,
diuresis
↑Cell viability
↓Cell apoptosis
In vitro ischemic reperfusion model by the ↓TBARS
Various plants and herbs, e.g., in essential anaerobic chamber method. Firstly, ischemia ↓KIM-1
HK2 cells Antioxidant, antiapoptotic Posttreatment [111]
oil of Matricaria chamomilla was induced for 24 h followed by 3 h ↑Cell viability
reperfusion. ↑GSH
Inhibit NADPH oxidase 4
↓SCr, BUN, renal KIM-1
↓MDA, MPO, IFN-c,
Bilateral ischemia for 45 min followed by 6 h
Acai fruit extract Euterpe oleracea Male Wistar albino rat Antioxidant, antiinflammatory caspase-3 [112]
reperfusion
↓Collagen IV, endothelin-1
↑IL-10
Oral route
↓IFN-Υ, IL-1β, caspase-3
pretreatment
↓NF-κB expression (in-vitro
C57BL/6 mice RAW264.7 Bilateral ischemia for 45 min followed by 24 h By regulating PI3K/Akt/mTOR signaling and NF- & in-vivo)
Aloperine Sophora alopecuroides [113]
and HK2 cells reperfusion κB transcriptional activity ↓PI3K/AkT/mTOR pathway
signaling
↑IL-10, SOD
↓SCr, BUN, MDA
↑SOD and GPx levels in vivo
and in vitro
↑JAK2 and STAT3
Male Sprague Dawley rat Bilateral ischemia for 45 min followed by 24 h Intraperitoneal route phosphorylation in vivo and
Apigenin Celery parsley wheat sprouts Activation of the JAK2/STAT3 pathway [114]
NRK-52E cells reperfusion pretreatment in vitro
↑Bcl-2 and procaspase-3
expression
↓Bax and caspase-3
expression
↓Urine volume
↑Urine osmolality
+ +
Bilateral ischemia for 45 min followed by 4 By upregulation of water channels and Na K Oral route ↑Urinary Na+, K+, Cl-
Aqueous extract Cuscuta chinensis (seeds) Male Sprague Dawley rat [115]
days reperfusion ATPase Posttreatment ↑Creatinine clearance
↑AQP-2, AQP-3 expression
↑Na+K+ ATPase
Oral route ↓SCr, BUN, MDA, MPO
Unilateral ischemia in the left kidney for 60
Aqueous extract Murraya koenigii (leaves) Male Wistar albino rat Antioxidant pretreatment and ↓Proteinuria [116]
minutes followed by reperfusion
posttreatment ↑SOD, CAT, GSH
↓IL-1β, IL-6, TNF-α
↓IL-10
Bilateral ischemia for 30 min followed by 24 h Oral route
Arctigenin Arctium lappa (fruit) Male C57BL/6 mice Anti-inflammatory effect ↓TLR4/Myd88 protein [117]
reperfusion pretreatment
expression
↓NF-κB expression
↓SCr, BUN, LDH, MDA
Potatoes, green leafy vegetables, root Right nephrectomy with left renal ischemia Intraperitoneal route ↓Renal histopathological
Ascorbic acid Male Sprague Dawley rat Inhibiting oxidative stress [118, 119]
vegetables, citrus fruits etc. for 45 min followed by 3 h reperfusion pretreatment score
↑GSH
Evidence-Based Complementary and Alternative MedicineTable 1: Continued.
Route of
Substance used Source Experimental model Ischemia Mechanism Administration and Effects Reference
order
↓SCr, BUN, MDA, MPO
↓Na-K-ATPase and Ca-
ATPase
↓KIM-1 and TNF-α mRNA
Berberis vulgaris, Hydrastis canadensis, Right renal nephrectomy and left kidney
Nephroprotection by caspase mitochondria Oral route expression
Berberine Coptis chinensis, Arcangelisia flava, B. ischemia for 45 min followed by 4 weeks [30]
dependent pathway posttreatment ↓Bax,
aquifolium, B. aristata reperfusion
↓Caspase-3 mRNA
expression
Male Wistar albino rat ↑Renal SOD and GSH
↑Bcl2 mRNA expression
↓SCr, BUN, LDH, MDA
Right nephrectomy with left renal ischemia Inhibit leukocyte apoptosis and upregulation of Intraperitoneal route ↓TNF-α, MPO
Betulinic acid Betula alba (bark) [120]
for 45 min followed by 6 h reperfusion Na+K+ ATPase pretreatment ↓Leukocyte apoptosis
↑Na+K+ ATPase, GSH
Commonly found in grains, fruits, and ↓SCr, BUN, MDA,
Bilateral ischemia reperfusion for 90 minutes Inhibit 5-lipoxygenase pathway. Anti- Oral route
Caffeic acid dietary add-ons as simple esters with ↓TNF α [121]
followed by reperfusion for 24 hours inflammatory and antioxidant effect pretreatment
quinic acid or saccharides ↑Catalase, SOD
↓SC, MDA, NO
Bilateral ischemia for 30 min followed by 24 h Antioxidant, anti-inflammatory, antiapoptotic Intravenous pre- and ↓iNOS, TNF-α, COX-2
Cannabidiol Cannabis sativa Male Sprague Dawley rat [122]
reperfusion activity posttreatment ↓ NF-κB, FasL caspase-3
↑GSH
↓SCr, BUN, cystatin C
↓MDA, NO
↓Total oxidant status
Bilateral ischemia for 45 min followed by 24 h
Evidence-Based Complementary and Alternative Medicine
Curcumin Curcuma longa Male Wistar albino rat Antioxidant, free radical scavenging ↑SOD, GPx (serum and [123]
days reperfusion
renal)
↑Catalase (renal)
Oral route ↑Total antioxidant capacity
pretreatment ↓SCr, BUN
↓TLR4, MyD88, TRAF6 in
Male Sprague Dawley rat vitro and in vivo
Bilateral kidney ischemia for 45 min followed Inhibiting theTLR4/MyD88 signaling pathway via
Dioscin Dioscorea nipponica NRK-52E and the HK- ↓IL-1, IL-6, TNF-α, ICAM-1 [124]
by 24 h reperfusion upregulation of HSP70
2 cells ↓IFN-Υ in vitro and in vivo
↑HSP 70 in vitro and in vivo
↑Cell viability
↓SCr, BUN
↓TNF-α, IL-6, IL-1β
Epigallocatechin Right nephrectomy and left kidney ischemia Anti-inflammatory suppressing NF-κB decreasing Intraperitoneal route
Camellia sinensis ↓Cleavage caspase-3 and Bax [125]
gallate for 45 min followed by 24 h reperfusion apoptosis pretreatment
↑Caspase-3 and BCL-2
Male Sprague Dawley rat
Suppressing NF-κB
Oral route ↓SCr, urea
Bilateral ischemia for 45 min followed by
Apium graveolens (leaves and stem) Antioxidant and anti-inflammatory pretreatment and ↑SOD and nitrogen oxide [126]
reperfusion
posttreatment level
↓SCr, BUN, LDH, MDA
Unilateral ischemia for 1 hour followed by Oral route
Crateva nurvala (leaves and bark) Antioxidant and anti-inflammatory ↑NR-F2, GSH [27]
24 h reperfusion pretreatment
↓TNF-α, IL-6, caspase-3
↓SCr, BUN, MDA
Bilateral ischemia for 45 min followed by 15 h
Sonchus oleraceus Antioxidant and anti-inflammatory ↑SOD [110]
Male Wistar albino rat reperfusion
↓IL-6, IL-1β, TNF-α
Ethanolic extract
Pretreatment ↓SCr, urea, uric acid
Bilateral ischemia for 60 min followed by 24 h ↓Renal tissue hemorrhage
Brassica rapa (roots) Anti-inflammatory antioxidant [127]
reperfusion ↓Necrosis and tubular
distention
Left renal ischemia for 45 min with right renal ↓SCr, BUN, MDA
Hypericum perforatum (flowering herb) Male Sprague Dawley rat Antioxidant and anti-inflammatory [105]
nephrectomy followed by 3 h reperfusion ↑SOD, catalase, GPx
Intraperitoneal route
↓SCr, BUN, MDA,
Bilateral renal ischemia for 30 min followed pretreatment
Petroselinum cripum Male Wistar albino rat Attenuating oxidative stress and inflammation ↓NO, ICAM-1, TNF-α [128]
by reperfusion for 24 hours
↓Leukocyte infiltration rate
78
Table 1: Continued.
Route of
Substance used Source Experimental model Ischemia Mechanism Administration and Effects Reference
order
↑Glomerulus dimeter, FRAP
level
↓SCr, BUN, MDA
Bilateral ischemia for 60 min followed by
Salvia miltiorrhiza Antioxidant anti-inflammatory ↓IL-6, IL-8, TNF-α [129]
30 min reperfusion
↑GSH, SOD, catalase, GPx
↓SCr, BUN, MDA
Bilateral ischemia for 30 min followed by 24 h ↓Na+, K+ excretion, FRAP
Tribulus terrestris Male Sprague Dawley rat Antioxidant [130]
reperfusion ↑Urine osmolality,
Oral route ↑Creatinine clearance
pretreatment
↓SCr, serum urea
↓Renal and urine MDA,
Right nephrectomy and left kidney ischemia By reducing oxidative stress, eNOS, and heme- GSH
Dalbergia ecastaphyllum Male Wistar albino rats [131]
for 60 min followed by 48 h reperfusion oxygenase upregulation Restores eNOS expression
↑Heme-oxygenase
expression
↓SCr, BUN, caspase-3
Commelinid plants, grasses, grains, ↓IL-1β, TNF-α, MPO
vegetables, flowers, fruits, leaves, beans, Bilateral ischemia for 35 min followed by 24 h activity
Ferulic acid Male C57/BL6 mice Increasing adenosine generation via HIF-1α [132]
seeds of coffee, artichoke, peanut, and reperfusion ↑Adnesine activity
nuts ↑CD 73, CD 39
↑HIF-1α mRNA
↓SC, urea, FENa+, FEK+
Right nephrectomy with left renal ischemia ↓Renal histopathological
Garlic juice Antioxidant, antiapoptotic [133]
for 45 min followed by 24 h reperfusion score
Allium sativum (bulbs) ↑Urinary creatinine
↓SC, Urea, Cystatin C
Bilateral ischemia for 45 min followed by 6 h
Garlic oil Antioxidant, anti-inflammatory ↓Oxidative stress index [134]
days reperfusion
↓MPO, NO
↓SC, urea, FENa+
↑Urinary creatinine and
Right nephrectomy with left renal ischemia urea
Ginger Zingiber officinale Antioxidant, anti-inflammatory [135]
for 45 min followed by 24 h reperfusion Oral route ↑Urinary K+ excretion
pretreatment ↓Renal histopathological
score
↓MDA
Unilateral ischemia in left kidney for 60
Ginkgo biloba ↓Necrosis and cast
Ginkgo biloba minutes followed by 60 minutes of Antioxidant [136]
EGb761 extract formation
reperfusion
↑SOD, CAT
Male Wistar albino rats ↓SCr, BUN
Bilateral ischemia for 45 min followed by 24 h
Rosa canina (fruits) Antioxidant, anti-inflammatory ↓Renal tissue [137]
reperfusion
histopathological score
↓SCr, BUN, MDA
↓Lymphocytes infiltration
Hydroalcoholic Bilateral ischemia for 30 min followed by 24 h
Crocus sativus Antioxidant and anti-inflammatory ↓TNF-α, ICAM-1 mRNA [138]
extract reperfusion
expression
↑FRAP
↓SCr, BUN, MDA
Bilateral renal ischemia for 45 min followed
Juglans mollis (bark) Antioxidant and anti-inflammatory. ↑SOD [109]
by 15-hour reperfusion
↓TNF-α, IL-1β, IL-6
↓SCr, BUN, MDA
↓TNFα, IL1β, IL10
Right nephrectomy followed by renal
Intraperitoneal ↓Apoptotic cells
Lavender oil Lavandula angustifolia ischemia for 45 min followed by reperfusion Attenuating oxidative stress and inflammation [100]
posttreatment ↓Total histopathological
for 24 hours
score
↑SOD, GPx, catalase
Liposomes Bilateral ischemia for 30 min followed by 24 h Targeted cellular delivery to renal tubular Intravenous Suppress NF-lB activity
Curcuma longa Male C57BL/6 mice [139]
containing curcumin reperfusion epithelial cells and antigen presenting cells pretreatment ↓SC, urea,
Evidence-Based Complementary and Alternative MedicineTable 1: Continued.
Route of
Substance used Source Experimental model Ischemia Mechanism Administration and Effects Reference
order
conferring protection from IR injury, mediated by ↓Renal histopathological
NF-kB score
↓TNF-α, CCL5, CCL2,
CXCL2
↓iNOS
↑SOD
↓SCr, BUN, MDA
↑SOD, CAT, GSH
Carrots, peppers, celery, olive oil,
↓TNF-α, IL-1β, IL-6
Luteolin peppermint, thyme, rosemary, and Bilateral ischemia Antioxidant and anti-inflammatory Pretreatment [106]
↓Bax and caspase-3
oregano
expression
↑Bcl-2 expression
Male Swiss albino mice
↓ Scr, blood urea, plasma
NGAL
Tomato, apricots, papaya, pink grapefruit, Bilateral renal ischemia for 30 min followed Intraperitoneal ↓Tissue Bax concentration
Lycopene Antioxidant and anti-inflammatory [140]
guava, and watermelon by reperfusion for 2 hours pretreatment ↓F21sop,
↓Notch2/HeS1
↓Renal TLR 2, renal IL-6
↓SCr, BUN,
↓Plasma potassium (K+)
↓ Caspase-3 mRNA
Mangifera indica also present in 16 other
Left nephrectomy and right kidney ischemia Anti-inflammation and inducing adenosine Oral route expression
Mangiferin plant families including Anacardiacae, Male C57/BL6-mice [141]
for 30 min followed by 24 h reperfusion production pretreatment ↓TNF-α, IL-1β
Gentianaceae, and Iridaceae
↓NO, MPO
Evidence-Based Complementary and Alternative Medicine
↑Adenosine and CD73
expression
↓SC
Right nephrectomy with left renal ischemia ↓Renal tissue
Aruncus dioicus (whole plant) Antioxidant, antiapoptotic [142]
for 40 min followed by 24 h reperfusion histopathological score
Intraperitoneal route
↓Bcl-2/Bax ratio
pretreatment
↓SC
Right nephrectomy with left renal ischemia
Cassia mimosoides var. Nomame Male Sprague Dawley rat Antioxidant ↓Caspase-3 [143]
for 40 min followed by 24 h reperfusion
Methanolic extract ↓Bcl-2/Bax ratio
↓SCr, FENa+, Creatinine
Left renal ischemia for 45 min with right renal clearance
Stevia rebaudiana Antioxidant and anti-inflammatory [144]
nephrectomy ↓MDA
↑GSH, Catalase
Bilateral ischemia for 60 min followed by 6 h ↓SCr, BUN, uric acid, MDA
Benincasa cerifera (fruits) Female Wistar albino rat Free radical scavenging activity [145]
reperfusion ↑SOD, catalase, GSH
↓SCr, BUN, cystatin c.
Oral pretreatment ↓MDA, NO
↓Renal histopathological
score
Bilateral ischemia for 60 min followed by 24 h
Nigella sativa oil Nigella sativa (seeds) Antioxidant, free radical scavenging. ↓Total oxidant status [146]
reperfusion
↑SOD, GPx (serum and
renal)
↑Catalase (renal)
Male Wistar albino rat ↑Total antioxidant capacity
↓SCr, BUN, renal KIM-1
↓LDH, MDA, caspase-3
expression
Olea europaea, Viscum album, Aralia Bilateral renal ischemia for 45 min followed Antioxidant, anti-inflammatory reductions in Nrf- Intraperitoneal route
Oleanolic acid ↓IFN-c, IL-6, MPO [85]
chinensis, >120 other plant species by 6 h reperfusion 2 pretreatment
↑SOD, GST, GPx and CAT
↑IL-10
↑Nrf-2
Osajin Maclura pomifera Antioxidant [147]
9Table 1: Continued.
10
Route of
Substance used Source Experimental model Ischemia Mechanism Administration and Effects Reference
order
↑SOD, GSH-Px (serum)
↑Total antioxidant capacity
Unilateral ischemia in left renal artery for
↓Renal histopathological
60 min followed by 10 min reperfusion
score effectively at a dose of
10 mg
↓SCr, BUN
Right nephrectomy and unilateral ischemia in
Cnidium monnieri, Angelica pubescens, ↓Caspase-3
Osthole left kidney for 45 min followed by 1, 6, and Antioxidant, antiapoptotic [148]
Peucedanum ostruthium ↑SOD, CAT
24 h reperfusion
↑Bcl-2/Bax ratio
↓MDA (maximal at
120 min)
Unilateral ischemia in left renal artery for Oral route ↑GSH (maximal at 240 min)
Picroliv Picrorhiza kurrooa (roots and rhizome) Male Sprague Dawley rat 60 min followed by 5, 60, 120, and 240 min Antioxidant, antiapoptotic pretreatment ↑GPx, SOD [149]
reperfusion ↓NO
↓Renal ICAM-1
↓Apoptosis
↓SCr, BUN, MDA
↓TNF-a and ICAM-1
Bilateral renal ischemia for 30 min followed mRNA expression
Piperine Piper nigrum (seeds) Attenuating oxidative stress and inflammation [104]
by reperfusion for 24 hours ↓Total histopathological
Male Wistar albino rat score
↑Total FRAP level
Polysaccharide Bilateral ischemia for 45 min followed by 24 h ↓SCr, BUN, LDH, MDA
Dipsacus asperoides (roots) Antioxidant [150]
extract reperfusion ↑SOD, CAT, GPx
↓Caspase-3 expression
Male BALB/c mice primary Antioxidative stress and anti-inflammation by ↑Shh mRNA expression (in
Unilateral ischemia in left kidney for 30 min Intraperitoneal route
Polydatin Polygonum cuspidatum (roots) renal tubular epithelial activating the sonic Hedgehog (SHH) signaling vivo and in vitro) [107]
followed by reperfusion pre and posttreatment
cells (RTECs) pathway ↑SOD, GST, GPx, and CAT
(in vivo)
↓SCr, BUN
↓Renal histopathological
score
↓Immune peroxidase
Bilateral ischemia for 30, 60, 90, and 120 min, Intravenous route labeling
Polyphenols Camellia sinensis White male rabbit Antioxidant, antinecrotic [151]
followed by 24 h reperfusion pretreatment of CD8+T cells in kidney
tissues
All the results were found
significant at 90 min of
ischemia
↓SCr, BUN
↓MPO, MDA
Polysaccharide Male C57BL/6J mice NRK- Left nephrectomy and right kidney ischemia Intraperitoneal route
Ganoderma lucidum (fruits) Counteracting oxidative stress ↓Bax/Bcl-2 ratio, [152]
peptide 52E cells for 35 min followed by 24 h reperfusion pretreatment
↑SOD, CAT, GSH and GPx
↑Cell viability
↓SCr, Serum urea, MDA
↑SOD,
Bilateral renal ischemia for 45 min followed Antioxidant and anti-inflammatory inhibiting
Polysaccharides Lycium barbarum Wistar albino rat ↓Serum IL-1β, TNF-α [28]
by 24 h reperfusion apoptosis
Enhanced renal expression
Oral route of Bcl-2 mRNA
pretreatment ↓SCr, BUN, AST
↓MDA, NOx
Bilateral ischemia for 60 min followed by 6 h
Proanthocyanidin Grape seed Male Sprague Dawley rat Decreasing oxidative and nitrosative stress ↓Renal histopathological [153]
reperfusion
score
↑SOD, GPx
Right nephrectomy with left renal ischemia Antioxidant, anti-inflammatory; inhibit Intraperitoneal route ↓SCr, BUN, MDA
Pycnogenol Pinus maritima (fresh bark) Male Wistar albino rat [154]
for 45 min followed by 3 h reperfusion neutrophil infiltration pretreatment ↓TNF-a, IL-1β, and IL-6
Evidence-Based Complementary and Alternative MedicineTable 1: Continued.
Route of
Substance used Source Experimental model Ischemia Mechanism Administration and Effects Reference
order
↓MPO
↓Renal histopathological
score
↑GSH, Na+K+ ATPase
↓Blood urea, SCr, plasma
NGAL
Apples, berries, Brassica vegetables,
↑BCl-2 level
capers, grapes, onions, shallots, tea, Bilateral renal ischemia for 30 min followed
Quercetin Male Swiss albino mice Attenuating oxidative stress and inflammation ↓Tissue Bax concentration [155]
tomatoes seeds, nuts, flowers, barks, and by reperfusion for 24 hours
↓F2-isoprostane
leaves
↓Renal notch-1 jagged-1
level
↓Mortality rate
↓SCr
Bilateral ischemia for 40 min followed by 24 h Intravenous route ↓TBARS
Resveratrol Grapes, wine, peanuts, soy Antioxidant, free radical scavenging [156, 157]
reperfusion pretreatment ↓Renal histopathological
score
Male Wistar albino rat ↑NO
Evidence-Based Complementary and Alternative Medicine
↓SCr, BUN, MDA
Bilateral ischemia for 60 min followed by 6 Oral route ↑SOD, catalase
Rhizome extract Coptidis japonica (rhizome) Antioxidant [17]
and 24 h reperfusion pretreatment ↑GSH (renal)
↓DNA fragmentation rate
Right nephrectomy and ischemia in the left
↓MDA, MPO
Rosmarinic acid Rosmarinus officinalis, Melissa officinalis Male Sprague Dawley rat kidney for 60 min followed by 60 min By decreasing oxidative stress [158, 159]
↑SOD, GPx
reperfusion
Intraperitoneal route
↓SCr, BUN, LDH, MDA
pretreatment
Buckwheat and many vegetables, fruits, Right nephrectomy with left renal ischemia ↓Renal histopathological
Rutin Male Wistar albino rat Decreasing oxidative stress, anti-inflammatory [160]
beverages such as tea and wine for 45 min followed by 3 h reperfusion score
↑GSH, MnSOD
↓SCr, BUN, MDA
↓Caspase-3 expression
Left renal nephrectomy and right kidney Inhibiting tubular cell death and inflammatory ↓Infiltration of Ly6G+
Sesamin Sesamum indicum (seed and oil) Male C57/BL6 mice ischemia for 30 min followed by 24 h response, upregulating CD39-adenosine-A2AR neutrophils [161]
reperfusion signals ↓MPO activity
↓TNF-α, IL-1β
↑Adenosine level
↓Tubular dilatation
↓Tubular vacuolization
Right nephrectomy with left renal ischemia Anti-inflammatory, antinecrosis, free radical Oral Pre-treatment
Silymarin Silybum marianum Male Sprague Dawley rat ↓Inflammation [162, 163]
for 45 min followed by 6 h reperfusion scavenging
↓Tubular and glomerular
necrosis
↓SCr, BUN, MDA,
↓Levels of Keap 1 and NF-
NRK-52E cells male Bilateral renal ischemia for 45 min followed KBP65
Total flavonoids Rosa laevigata Attenuating oxidative stress and inflammation [108]
Sprague Dawley rat by reperfusion for 24 h ↓IL-1β, IL-6, TNF-α
↑Sirt 1, Nrf 2, and HO 1
↑GSH, GPx, SOD
↓SCr, Angiotensin II
Crataegus sp., Arctostaphylos uva-ursi, ↓STAT3 protein
Right renal nephrectomy and left kidney Decrease in oxidative stress. Suppressing STAT3,
Ursolic acid Chinese elder herb, Actinidia deliciosa, Male Sprague Dawley rat Posttreatment phosphorylation [164]
ischemia for 45–90 minutes NF-κB and caspase-3 activities.
Prunella vulgaris ↓NF-κB expression
11
Inhibit caspase-3 activity12 Evidence-Based Complementary and Alternative Medicine
1 oxide synthase (iNOS), and the transcription of in-
H2 O2 ⟶ GPx H2 O + O2 . (3) flammatory cytokines and chemokines [173, 174]. The peak
2
levels of NF-κB in rat models of renal I/R injury AKI were
A number of plant-derived extracts and natural com- found after 15 minutes of reperfusion [173]. Therefore,
pounds (Table 1) are able to increase the levels of these inhibiting the NF-κB-mediated inflammatory pathway is
antioxidant enzymes, thereby providing protection against another approach to ameliorate I/R injury induced-AKI
RIRI-induced AKI. There are numerous plants, which in- inflammation [175]. Many plant-derived compounds were
crease the levels of SOD as shown in example (Table 1) found to inhibit or decrease the levels of NF-κB expression
[28, 30, 109, 110, 126]. Similarly, some plant extracts were such as ursolic acid [164], epigallocatechin gallate [125],
reported to increase both SOD and catalase levels aloperine [113], arctigenin [117], and cannabidiol [122]
[106, 116, 121, 136, 148], while others were reported to (Table 1). The effects of renal ischemic reperfusion (I/R)
increase all the three antioxidant enzymes SOD, catalase, induced acute kidney injury (AKI) and administration of
and GPx [85, 105, 107, 123, 129, 146, 150, 152]. It is therefore plant-derived extracts and compounds on kidney have been
concluded that different plants exhibited their own mech- illustrated in Figure 1.
anism of protection (Table 1).
Antioxidant compounds such as glutathione (GSH)
modify the cell response against ROS generation in I/R 4.3. Increasing Adenosine Levels. Adenosine is an endoge-
injury-induced AKI. GSH plays an important role in both nous nucleotide composed of adenine and ribose. Adenosine
the detoxification of drug metabolites and the regulation of plays an important role against hypoxia as a result of renal I/
gene expression and apoptosis [167]. Depletion of GSH R injury [176, 177]. Adenosine regulates essential kidney
levels lead to an increase in oxidative stress and is directly functions such as the glomerular filtration rate (GFR), renin
associated with I/R injury [168]. A number of plants as release, and tubular glomerular feedback mechanisms [178].
shown in Table 1 were reported to increase the levels of GSH, Adenosine produces its effects on kidney via the stimulation
thereby protecting kidney from ROS generated by I/R injury of adenosine receptors (AR), which has four subtypes
[27, 111, 118, 120, 122] (Table 1), and were reported to (A1AR, A2AAR, A2BAR, and A3AR). Necrosis, apoptosis,
increase the levels of GSH, SOD, and catalase [116, 145], and inflammation due to renal I/R injury induced-AKI are
while some others have been found to increase GSH, GSH- reduced by adenosine via stimulation of the A1AR receptor
Px, SOD, and catalase [152]. Thus, plants exhibited versatile [179]. Adenosine has 100 times more affinity to bind with
mechanisms of protection. A1AR and A2AR receptors compared to the other two
subtypes of AR receptors. Stimulation of both A1AR and
A2AR receptors play a role in controlling inflammation after
4.2. Decreasing Anti-Inflammatory Cytokines. The dying and renal I/R injury-induced AKI [180].
injured cells as a consequence of renal I/R injury release Various plant-derived extracts and compounds (Table 1)
proinflammatory cytokines such as interleukins and tumor were reported to increase the levels of adenosine activity.
necrosis factor (TNF) and chemotactic cytokines (CCL5, Pretreatment with sesamin [161], mangiferin [141], and
CCL2, and CXCL2). There is also an activation of some ferulic acid [132] remarkedly increased adenosine levels in
transcription factors such as heat shock proteins (HSP), high the I/R treatment group compared to the renal I/R injury
mobility group box-1 (HMGB1), and hypoxia-inducible AKI group. Increases in adenosine levels were accompanied
factor-1 (HIF1) [169, 170]. These factors are responsible for by a decrease in caspase-3 expression and inflammatory
the stimulation of cell surface receptors, which in turn cytokine levels, which shows a reduction in apoptosis, ne-
triggers inflammatory and cytotoxic reactions [171]. crosis, and inflammation, respectively.
Plant-derived extracts and natural compounds target
proinflammatory cytokines to halt inflammation and 4.4. Other Mechanisms. The phosphatidylinositol-3-kinase
ameliorate renal I/R injury-induced AKI. The main in- (PI3K)/Akt/mTOR pathways play a significant role in cell
flammatory cytokines and chemokines which are decreased survival processes such as apoptosis, metabolism, and an-
by plant-derived extracts include tissue necrosis factor alpha giogenesis. These pathways are so interrelated that, in many
(TNF-α), interleukin-1β (IL-1β), interleukin-10 (IL-10), circumstances, they are regarded as a single pathway
interleukin-6 (IL-6), interleukin-8 (IL-8), and interferon [181, 182]. The PI3K/Akt/mTOR signaling is assumed to be
gamma (IFN-c) [172]. Natural compounds that decrease the involved in renal I/R injury-induced inflammation
levels of TNF-α, IL-1β, and IL-6 include arctigenin [117], [183, 184]. Among the compounds listed in Table 1, only
luteolin [106], epigallocatechin gallate [125], pycnogenol aloperine was found to regulate the PI3K/Akt/mTOR
[154], and ferulic acid [132] as well as plant-derived extracts pathway and have markedly reduced its signaling compared
such as Juglans mollis [109] and Sonchus oleraceus [110] to renal I/R injury AKI group [113].
(Table 1). Another pathway known as Janus kinase/signal trans-
The TNF-α induces proinflammatory effects by acti- ducers and activators of transcription (JAK/STAT) is es-
vating transmembrane TNF-α receptors, causing the stim- sential for growth hormone and other cytokine signaling.
ulation of the nuclear factor-κB (NF-κB). NF-κB is The cytokines bind to their receptors and activates JAK,
responsible for the expression of over 400 genes including which then causes the phosphorylation of STAT. The STATs
cyclooxygenase-2, lipoxygenase-2 (LOX-2), inducible nitric are then transferred into the nucleus where they initiateYou can also read
