A Review of Natural Products for Prevention of Acute Kidney Injury

Background and Objectives: acute kidney injury (AKI), formerly called acute renal failure (ARF), is commonly defined as an abrupt decline in renal function, clinically manifesting as a reversible acute increase in nitrogen waste products—measured by blood urea nitrogen (BUN) and serum creatinine levels—over the course of hours to weeks. AKI occurs in about 20% of all hospitalized patients and is more common in the elderly. Therefore, it is necessary to prevent the occurrence of AKI, and to detect and treat early, since it is known that a prolonged period of kidney injury increases cardiovascular complications and the risk of death. Despite advances in modern medicine, there are no consistent treatment strategies for preventing the progression to chronic kidney disease. Through many studies, the safety and efficacy of natural products have been proven, and based on this, the time and cost required for new drug development can be reduced. In addition, research results on natural products are highly anticipated in the prevention and treatment of various diseases. In relation to AKI, many papers have reported that many natural products can prevent and treat AKI. Conclusions: in this paper, the results of studies on natural products related to AKI were found and summarized, and the mechanism by which the efficacy of AKI was demonstrated was reviewed. Many natural products show that AKI can be prevented and treated, suggesting that these natural products can help to develop new drugs. In addition, we may be helpful to elucidate additional mechanisms and meta-analysis in future natural product studies.


Introduction
Acute kidney injury (AKI) refers to a sudden decrease in renal function and decreased renal function is characterized by an increase in serum creatinine (sCr) levels and an abnormal decrease in urine output [1]. AKI, previously called acute renal failure (ARF), is a condition of sudden kidney failure in patients with or without preexisting chronic kidney disease (CKD); severe kidney dysfunction within a few hours or days results in a significant decrease (oliguria) or complete elimination of urine (anuria), with electrolyte imbalance, often requiring hemodialysis [2]. In AKI's population-based study using the risk, injury, failure, loss, end-stage kidney disease (RIFLE) criteria, the annual incidence of AKI was 2147 per million people. In another collaborative study, the annual incidence of non-dialysis and dialysis-dependent AKI was 3841 and 244 per million people, respectively [3]. In addition, if not treated immediately, AKI can lead to development of CKD overtime requiring replacement therapies such as dialysis and in the best-case kidney transplantation [4]. It is known that approximately 20% of patients with a history of AKI develop a chronic disease characterized by cardiovascular complications, and increased mortality. Various pathological mechanisms have been suggested that progression AKI and transition to CKD including anoxemia, thinning of microcirculation vessels, altered phenotype and

Research Method
In order to find research results on AKI and natural products, many papers published between 2010 and 2021 were searched for in electronic databases such as PubMed, Google Scholar, and Embase. We identified articles for further review in compounds by performing an initial screen of identified abstracts or titles about prevention against AKI. Papers were considered for inclusion if they were researched on anti-oxidant and anti-inflammatory effects. The keywords for the search were as follows: "acute kidney injury", "AKI", "natural product", "compounds", "plant", and "antioxidant". The papers finally selected for the literature review are shown in Table 1. Table 1. List of some natural products with potential prevention of AKI action.

Described Effects and Mechanisms References
Flavonoids Quercetin NRK-52E cells and HK-2 cells Treatment 10 µM Reducing the levels of malondialdehyde, lipid ROS and increasing the levels of glutathione [15] Luteolin Cisplatin-induced AKI in mice Treatment 50 mg/kg Increased the levels of p53 and its phosphorylation, decreased the levels of PUMA-α, Bax and caspase-3 activity [16] Apigenin Renal ischemia/reperfusion in rats

Pathophysiology of AKI
AKI is a clinical endpoint of many processes that lead to a decreased glomerular filtration rate and are indicators of general kidney function. Key components of the injury process include apoptosis, necrosis, reactive oxygen species (ROS), and microvascular injuries that cause local ischemia, endothelial dysfunction, leakage, and inflammation ( Figure 1) [45]. AKI is most commonly caused by ischemic or toxic damage and occurs in septic situations. Components of the pathophysiology are inflammatory reactions as well as tubular or vascular damage and their consequences [46].

Pathophysiology of AKI
AKI is a clinical endpoint of many processes that lead to a decreased glomerular filtration rate and are indicators of general kidney function. Key components of the injury process include apoptosis, necrosis, reactive oxygen species (ROS), and microvascular injuries that cause local ischemia, endothelial dysfunction, leakage, and inflammation (Figure 1) [45]. AKI is most commonly caused by ischemic or toxic damage and occurs in septic situations. Components of the pathophysiology are inflammatory reactions as well as tubular or vascular damage and their consequences [46]. Inflammation is mediated in part by the adhesion of leukocytes to diseased endothelial cells. Ischemic AKI is the most common cause of AKI in hospitalized patients, with an average mortality rate of 50% [47]. In response to injury, surface expression of the leukocyte adhesion molecules ICAM-1 and P and E selectins is increased on endothelial cells Inflammation is mediated in part by the adhesion of leukocytes to diseased endothelial cells. Ischemic AKI is the most common cause of AKI in hospitalized patients, with an average mortality rate of 50% [47]. In response to injury, surface expression of the leukocyte adhesion molecules ICAM-1 and P and E selectins is increased on endothelial cells [47][48][49]. In vivo imaging studies have shown that leukocytes adhere to the wall of peritubular capillaries within hours of reperfusion [50]. Treatment aimed at reducing endothelial/white blood cell interactions by targeting these endothelial adhesion molecules can maintain blood flow and prevent ischemia reperfusion induced nephropathy [47]. Endothelial cells can also be a source of chemokines such as fractalkine (CX3CL1), which is expressed after kidney injury, and can promote are infiltration of macrophages [47].

Natural Products for the Prevention of AKI
Since AKI is a multifactorial disease and can be associated with co-morbidities, there is no pharmacological approach in clinic to reverse the renal injury. Currently, maintenance of volume homeostasis and correction of biochemical abnormalities are still the goals for the treatment of AKI. Therefore, prevention is always critical for this disease. Some functional components from food materials have been reported to have the ability to protect renal functions, indicating long-term administration of these components might be an effective approach to prevent AKI [51].
As shown in Figure 1, the TGF-β receptor, TNF receptor, caspase-3, caspase-9, etc., then these receptors activate downstream pathways, further ROS production and inflammatory responses, eventually leading to kidney damage. Several effective natural products suppress cisplatin, lipopolysaccharide (LPS), Ischemia-Reperfusion (I/R)-stimulated inhibiting the NF-κB pathway and reducing inflammation. Moreover, some compounds reduce apoptosis by inhibiting TGF-β, Akt, and p53 pathways. Additionally, some compounds can reduce ROS production.
Many compounds, including flavonoids, polyphenols, terpenes, alkaloids, saponins, and quinones, have multiple beneficial pharmacological activities such as antioxidants and anti-inflammatories [52]. Oxidative stress is considered an AKI factor. Natural products derived from plants have strong anti-inflammatory and antioxidant properties. There have been many studies to investigating the effect of common herbal extracts and their constituents on AKI [53]. This section discusses extracts of several plants and isolated compounds used for the prevention and treatment of AKI.

Flavonoids
Flavonoids are found in many plant foods, including vegetables, fruits, and herbs. The flavonoid activity depends on the structure of the hydroxylated phenol [54]. Flavonoids are known to have anti-cancer, anti-inflammatory, and antioxidant effects [55][56][57].
Quercetin is a naturally occurring flavonoid compound commonly found in more than 20 fruits and vegetables and is the most abundant in the diet. It has been of medical interest because it is known for its pharmacological effects such as anti-inflammatory, antihypertensive, vasodilator, anticholinergic, and anti-atherosclerosis treatment [58]. Y. Wang et al. reported that quercetin inhibited ferroptosis in renal proximal tubular epithelial cells. This compound blocked the typical morphologic changes of ferroptotic cells by reducing the levels of malondialdehyde (MDA) and lipid ROS and increasing glutathione levels [15].
Luteolin is a flavonoid component found not only in peanut shells, but also in parsley, celery, pepper, and chamomile, and is known to have anticancer, anti-inflammatory, and antioxidant effects [59]. Treatment with luteolin in mice treated with cisplatin can significantly improve renal dysfunction and reduce renal tubular cell damage, oxidative stress, and apoptosis [16].
Apigenin is found in herbs such as thyme and parsley, and in orange, peppers. It can improve I/R damage to the heart, brain and liver of rats, as well as epithelial cells of the proximal tubules of the human kidney in vitro. medicine. It can also reduce induced nephrotoxicity [60]. X. Wang et al. reported that apigenin significantly up-regulates the expression of B-cell lymphoma 2 (Bcl-2) and phosphor-Akt (p-Akt), Phosphoinositide 3-kinase (PI3K), while down-regulating the expressions of Caspase3 and Bax induced by hypoxia/reoxygenation injury [17].
Kaempferol is a natural dietary flavonoid compound with many adaptive biological activities, including antioxidant and estrogenic activity. Z. Wang et al. evaluated the effect of kaempferol on mechanisms related to nephrotoxicity in a cisplatin-induced AKI mouse model. Pretreatment with kaempferol has been observed to reduce kidney damage [18].
Icariin is the main active flavonolic glycoside of the epimedium. It is widely used in medical treatment due to its anti-tumor properties and potential for and osteoporosis treatment and has been shown to slow cell aging [61,62]. Icariin may improve urinary protein excretion and renal tissue damage in pregnancy induced hypertension rats, and its main mechanism is mediated in part by the up-regulation of nephrin expression and down-regulation of Ang II [19].
Myricetin is commonly found in fruits, berries, and vegetables. It has been shown to have a variety of biological activities, including antioxidant and anti-inflammatory effects [63]. Milicetin significantly increases GSH level and caspase activity, and at the same time improves renal tissue histopathology and significantly decreases levels of blood urea nitrogen (BUN), serum creatinine, caspase-3, TNF-α, IL-6, COXI, COXII and MDA. This study suggests a protective and promising prophylactic strategy to prevent nephrotoxicity [20].

Polyphenols
Polyphenols are found in vegetables, fruits, grains, chocolate, and beverages such as wine, coffee, black tea, and green tea [64]. Growing research shows that polyphenols may play an important role in health by regulating body weight, chronic disease, cell proliferation, and metabolism [65]. Epidemiological studies in humans and animals have shown that various polyphenols have anti-inflammatory and antioxidant properties, as well as therapeutic and prophylactic effects in obesity, cancer, cardiovascular, and neurodegenerative diseases [66][67][68][69].
Ellagic acid is an antioxidant and anti-inflammatory polyphenol compound found in

Polyphenols
Polyphenols are found in vegetables, fruits, grains, chocolate, and beverages such as wine, coffee, black tea, and green tea [64]. Growing research shows that polyphenols may play an important role in health by regulating body weight, chronic disease, cell proliferation, and metabolism [65]. Epidemiological studies in humans and animals have shown that various polyphenols have anti-inflammatory and antioxidant properties, as well as therapeutic and prophylactic effects in obesity, cancer, cardiovascular, and neurodegenerative diseases [66][67][68][69].
Chlorogenic acid is one of the most readily available phenolic compounds in coffee, tea and other foods, and a well-known antioxidant [73]. This compound dose-dependently attenuated LPS-induced kidney histopathologic changes, serum BUN, and creatinine levels, and also suppressed LPS-induced TNF-α, IL-6, and IL-1β production both in serum and renal tissues [26].
Gallic acid is a low-molecular weight triphenol compound that has been shown to have strong antioxidant activity in many studies [74][75][76]. It provides effective protection against oxidative damage caused by active substances commonly found in biological systems [77,78]. Ahmed Vander H et al. reported that pretreatment with gallic acid can significantly increase levels of renal MDA, serum glutathione, and glutathione peroxidase activity after renal ischemia-reperfusion injury [27].
Vanillic acid is a phenolic derivative obtained from edible plants and fruits with antibacterial, antifilarial and hepatoprotective properties [79,80]. Due to the presence of carboxyl groups, vanillic acid is an important antioxidant and inhibits inflammatory mediators, inhibiting NF-κB in mice stimulated with LPS [79]. Sindhu G et al. suggested that pretreatment with vanillic acid (50 and 100 mg/kg) restored elevated levels of kidney function markers and reduced antioxidant status to near normal when compared to mice treated with cisplatin alone [28].
Resveratrol is a polyphenolic substance that is produced when plants are exposed to adverse environmental conditions such as fungi and pests. It is derived from a variety of edible plants such as grapes, berries and peanuts [81]. Its anti-inflammatory effect may prevent AKI caused by sepsis [82]. Resveratrol significantly ameliorated serum creatinine.
BUN, and histopathological lesions induced by cisplatin. In addition, it leads to significantly increased expression of Fas ligand, tumor necrosis factor-α (TNF-α), caspase-8 and Bcl-2 associated protein X apoptosis regulator (Bax), and decreased expression of antiapoptosis regulators. Resveratrol administration significantly altered the cisplatin-induced changes in proteins associated with apoptosis [29].
Anthocyanins are water-soluble pigments that can be red, purple, blue or black depending on environmental pressure, such as solar radiation and low nitrogen content [83]. Anthocyanins contribute significantly to the antioxidant properties of some colored foods such as grapes and berries [84]. Li L. et al. showed that anthocyanins are effective against AKI by reducing inflammation, oxidative stress, lipid peroxidation and apoptosis [30].

Terpenoids
Terpenoids, also known as isoprenoids, are the largest type of secondary metabolites in plants, accounting for about 60% of phytochemicals [87]. They have a distinctive fragrance and are used in spices and in traditional pharmaceuticals for perspiration, antipyretic, and analgesic effects [88,89]. Terpenoids are also used for cancer treatment and prevention, cardioprotection, endocrinology/reproductive dysfunction, nutritional supplements, conventional medicine, immunology, anti-inflammation, menopause, and neuroprotection [90].
Glycyrrhetinic acid is an effective ingredient of Glycyrrhiza glabra L. (Liquorice). It is very sweet and is used extensively as a conditioner and flavoring agent to treat a variety of inflammatory conditions [91]. Sana M et al. reported that glycyrrhetinic acid has a protective effect on methotrexate-induced nephrotoxicity and the possible mechanisms for activating the Nrf2/ARE signaling pathway to reduce oxidative stress and inflammation [38].

Terpenoids
Terpenoids, also known as isoprenoids, are the largest type of secondary metabolites in plants, accounting for about 60% of phytochemicals [87]. They have a distinctive fragrance and are used in spices and in traditional pharmaceuticals for perspiration, antipyretic, and analgesic effects [88,89]. Terpenoids are also used for cancer treatment and prevention, cardioprotection, endocrinology/reproductive dysfunction, nutritional supplements, conventional medicine, immunology, anti-inflammation, menopause, and neuroprotection [90].
Glycyrrhetinic acid is an effective ingredient of Glycyrrhiza glabra L. (Liquorice). It is very sweet and is used extensively as a conditioner and flavoring agent to treat a variety of inflammatory conditions [91]. Sana M et al. reported that glycyrrhetinic acid has a protective effect on methotrexate-induced nephrotoxicity and the possible mechanisms for activating the Nrf2/ARE signaling pathway to reduce oxidative stress and inflammation [38].
Ursolic acid (UA) is a naturally occurring triterpene compound found in various plants such as fruits and vegetables. Ursolic acid has been studied for its beneficial effects, such as anti-inflammatory, antioxidant, anti-apoptotic, and anti-cancer effects [92]. Re- Ursolic acid (UA) is a naturally occurring triterpene compound found in various plants such as fruits and vegetables. Ursolic acid has been studied for its beneficial effects, such as anti-inflammatory, antioxidant, anti-apoptotic, and anti-cancer effects [92]. Recently, it was demonstrated that ursolic acid can treat sepsis in animal models [93]. According to a recent study, ursolic acid can protect against AKI-induced sepsis by inhibiting ROS and inflammatory cytokines, including TNF-α, IL-1β, and IL-6, in the kidneys of septic mice [39].
Oleanolic acid is a pentacyclic triterpenoid compound that is found in plant of the Oleaceae family such as the olive plant [94]. It is a natural product isolated from some food and medicinal plants. It is a triterpenoid that has many health benefits including antioxidant, anti-inflammatory, and anti-apoptotic effects [95]. Oleanolic acid inhibited the increase in proapoptotic caspase-3 and -9 activation and a simultaneous increase in poly (ADP-ribose) polymerase (PARP) cleavage activation in a concentration-dependent manner [40]. Genipin, pinitol, linalool, geraniol, malbiin, betulinic acid, butyric acid, and corosolic acid can also be used to prevent AKI and listed in Table 1 [41][42][43][44], while their chemical structures are shown in Figure 4. tic mice [39].
Oleanolic acid is a pentacyclic triterpenoid compound that is found in plant of the Oleaceae family such as the olive plant [94]. It is a natural product isolated from some food and medicinal plants. It is a triterpenoid that has many health benefits including antioxidant, anti-inflammatory, and anti-apoptotic effects [95]. Oleanolic acid inhibited the increase in proapoptotic caspase-3 and -9 activation and a simultaneous increase in poly (ADP-ribose) polymerase (PARP) cleavage activation in a concentration-dependent manner [40]. Genipin, pinitol, linalool, geraniol, malbiin, betulinic acid, butyric acid, and corosolic acid can also be used to prevent AKI and listed in Table 1 [41][42][43][44], while their chemical structures are shown in Figure 4.

Discussion
In this paper, 30 papers related to the prevention and treatment of AKI through natural products were reviewed. The AKI animal model was induced by drugs by cisplatin, LPS, Methotrexate, contrast, and glycerol. In addition, various induced-AKI models were tested, such as I/R injury, pregnancy, pancreatitis, and sepsis. Among the induced AKI models, 14 cases of cisplatin, 5 cases of I/R injury, LPS, and sepsis, 1 case of contrast, methotrexate, pregnancy-induced hypertension, glycerol, pancreatitis were tested. The main clinical features for evaluating renal function in AKI are an increase in sCr levels and BUN, and a decrease in urine output. In this case, 30 natural products tested in vivo showed the effect of reducing sCr levels and BUN, and this mechanism appeared was confirmed through various pathways. These pathways were involved in apoptosis, anti-oxidant, and inflammation.

Discussion
In this paper, 30 papers related to the prevention and treatment of AKI through natural products were reviewed. The AKI animal model was induced by drugs by cisplatin, LPS, Methotrexate, contrast, and glycerol. In addition, various induced-AKI models were tested, such as I/R injury, pregnancy, pancreatitis, and sepsis. Among the induced AKI models, 14 cases of cisplatin, 5 cases of I/R injury, LPS, and sepsis, 1 case of contrast, methotrexate, pregnancy-induced hypertension, glycerol, pancreatitis were tested. The main clinical features for evaluating renal function in AKI are an increase in sCr levels and BUN, and a decrease in urine output. In this case, 30 natural products tested in vivo showed the effect of reducing sCr levels and BUN, and this mechanism appeared was confirmed through various pathways. These pathways were involved in apoptosis, anti-oxidant, and inflammation.
Natural products medicine has been practiced to prevent, treat, and cure diseases for thousands of years. Natural products medicine involves using natural compounds, which have relatively complex active ingredients with varying degrees of side effects. Some of these herbal medicines are known to cause nephrotoxicity. Some of the nephrotoxic components from herbs are alkaloids, anthraquinones, flavonoids, and glycosides from natural compounds that cause kidney toxicity [96]. The kidney is the route of excretion of most of the substances present in the natural compounds. The high blood flow rate and sizeable endothelial surface area of the kidneys ensure delivery of large amounts of toxin to the renal parenchyma. High concentrations may be reached in the medulla because of active tubular transport, especially during a state of fluid deprivation. The exact incidence of kidney injury due to nephrotoxic natural compounds is not known.
It is worth noting that inflammatory and antioxidant compounds derived from natural products have therapeutic effects in the AKI-induced model by cisplatin, LPS, sepsis, renal I/R, and hypertension. Further studies are needed to determine the beneficial effects of specific products on humans and other animals with kidney disease to elucidate the detailed mechanisms of their renal protective effects. In addition, while certain natural products are excellent at preventing kidney damage in vitro and in vivo, it is necessary to further researches on the optimal dose to protect against a variety of renal damage.

Conclusions
AKI is a rapid loss in renal function over a period of hours to days, and a major worldwide health problem. As a result of the decline in renal function, nitrogenous wastes accumulate in the body, resulting in hypernatremia in the blood, and abnormalities in body fluid and electrolyte balance. AKI occurs in about 10% of hospitalized patients and about 30% of patients admitted to the intensive care unit. Despite advances in modern medicine, there are no consistent treatment strategies for preventing the progression to CKD. In this paper, we described the pathogenesis of AKI and the findings of natural products that may potentially assist us in prevention and treatment. So this review summarizes the studies on the effects of three types of natural products on AKI. Studies involving this review have mainly focused on anti-inflammatory and anti-oxidant properties. The causes and clinical features of AKI are very diverse. Hence, studies on natural products with preventive and therapeutic effects related to various causes of AKI should be continuously conducted.
The phytochemicals in medicinal plants have attracted significant attention due to the fewer side effects and being cost-effective. Many compounds such as flavonoids, polyphenols, and terpenoids are effective against induced AKI models. Although natural compounds play an essential role in preventing AKI, it is not yet clear whether these natural compounds can be used as drugs or dietary supplements.
In the future, more research is needed to evaluate the efficacy of plants in AKI prevention, and we expect that this review could be used as a basic paper for meta-analysis, the prevention and treatment of AKI afterward.