Nephroprotective activity of medicinal plants: A review on in silico-, in vitro-, and in vivo-based studies

INTRODUCTION

The kidneys are organs that play an essential role in the human body. In general, the kidneys function in several ways in the body, including acid-base balance, regulation of the endocrine system, blood pressure, and erythropoiesis (Al-Snafi & Talab, 2019). Abnormality in the kidneys will interfere with the regulatory function and change the homeostasis, which can be life-threatening (Dhondup & Qian, 2017). The Global Burden of Disease stated that nearly 1.2 million people die from kidney failure. This increased by 32% over the period of 2005–2015 (Luyckx et al., 2018), whereas according to GLOMMS-II and multinational databases, about 8%–18% or 22% of hospitalized patients are diagnosed with acute kidney injury (AKI). Most of these patients developed AKI within 2 days of being admitted to the intensive care unit (Hansrivijit et al., 2021).

Medication, such as anticancer drugs, is a common cause of kidney injury. The current drug-induced nephrotoxicity focuses on AKI. A prospective cohort study related to AKI due to drug exposure showed that the incidence of nephrotoxicity in adults was around 14%–26%, whereas 16% occurred in the hospital’s pediatric population. These incidents are more common in inpatients, especially intensive care patients (Perazella, 2018). The AKI incidence is a severe problem for healthcare professionals due to its high mortality rate (Kirkley et al., 2019; Park et al., 2018; Winther-Jensen et al., 2018).

AKI is a reversible condition with a sudden decrease in kidney function, an increase in serum creatinine and blood urea nitrogen, and a reduced-glomerular filtration rate (GFR) (Konda et al., 2016). AKI can develop into chronic kidney disease (CKD) if it is not detected or treated early. At the end-stage renal disease level, this is a severe condition that requires kidney transplantation or dialysis (Cho et al., 2018). Moreover, it can be defined that AKI is particularly related to an imbalance between oxygen and nutrients, which is caused by the occurrence of impaired microcirculation to the nephrons and increased energy requirements due to oxidative stress in the cells (Makris & Spanou, 2016). However, the concept of using antioxidants to prevent AKI is always interesting to be thoroughly discussed. This review focuses on plants with nephroprotective activity as confirmed by in silico, in vitro, and in vivo studies.

METHODS

Literature search was carried out by using the National Center for Biotechnology Information database with the following keywords: “nephroprotective activity” [Medical Subject Headings (MeSH) terms] or “medicinal plants” [all fields] and (“plants, medicinal”[MeSH Terms] or (“plants”[All Fields] and “medicinal”[All Fields]) or “medicinal plants”[All Fields] or (“medicinal”[All Fields] and “plant”[All Fields]) or “medicinal plant”[All Fields]) and (“computer simulation”[MeSH Terms] or (“computer”[All Fields] and “simulation”[All Fields]) or “computer simulation”[All Fields] or “silico”[All Fields] or “in silico”[All Fields]) and (“in vitro techniques”[MeSH Terms] or (“vitro”[All Fields] and “techniques”[All Fields]) or “in vitro techniques”[All Fields] or “vitro”[All Fields] or “in vitro”[All Fields]) and ((“in”[All Fields] and “vivo”[All Fields]) or “in vivo”[All Fields]) and “studies”[All Fields]. Additional references as supporting scientific data were searched using the same keywords.

PATHOPHYSIOLOGY OF AKI

The pathophysiology of AKI is multifactorial and complex, where the most widely recognized causes are ischemia, hypoxia, and nephrotoxicity (Basile et al., 2012). These causes are very influential on the kidneys resulting in vasoconstriction, endothelial damage, and activation of the inflammatory process. This impact affects the tubular blood vessels in the outer medulla of the kidney, where the partial pressure of oxygen becomes low, resulting in decreased renal blood flow (RBF) (Basile & Yoder, 2014). In a similar manner, serum or plasma creatinine affirmation is comprehensively used for AKI confirmation, yet there is a nondirect association between creatinine obsession and GFR (Thuraisingham & Adu, 2013). The increase in blood creatinine after AKI was due to a 90% decrease in creatinine clearance from baseline (Waikar & Bonventre, 2009).

During ischemia, AKI is specified into five phases (as shown in Fig. 1), which starts from the first phase, namely, the prerenal phase. The prerenal phase continues to the next stage if the RBF decreases but the cellular stability is maintained. Subsequently, the second phase, namely initiation, is characterized by a decrease in GFR due to decreased net ultrafiltration pressure. Ischemic injury is more concentrated in the S3 segment of the proximal tubule due to the high use of ATP in the area, resulting in a lower oxygen partial pressure. Moreover, ischemia causes ATP depletion, blocks sodium transport, produces reactive oxygen species (ROS), causes changes in cytoskeletal structure, and causes loss of cell polarity. The third phase is an extension, where a change in the structure and function of vascular endothelial cells and renal tubular epithelium occurs, resulting in the recruitment of inflammatory cells, including neutrophils, lymphocytes, and macrophages, as well as the expression of adhesion molecules and chemokines. S3-segment cells activate proinflammatory gene transcription via interferon-1 regulatory factor. On the other hand, proximal tubular cells producing cytokines (TNF-α, TGF-β, and interleukin), including IL-18 and IL-6, are also released into the tubular lumen and can be used as early markers of kidney damage. The following fourth phase is maintenance, which lasts for 1 or 2 weeks and usually occurs in oliguria and uremic. In addition, GFR during this phase is stabilized at the lowest level after reperfusion. Consequently, the cells undergo repair, migration, apoptosis, and proliferation in the efforts of cellular and tubule stability. The last phase is recovery; gradually in this phase, there are repair and regeneration of the tubular epithelium, as well as GFR toward a normal state (Hoste et al., 2015).

Figure 1. The relationship between GFR and serum creatinine (SCr) in the AKI phase. Adapted and modified from (Seller-Pérez et al. (2016), Sutton et al. (2002), and Mattei et al. (2016) . [Click here to view]

DRUGS THAT INDUCE AKI

THE ROLE OF NUCLEAR FACTOR-ΚB (NF-ΚB) SIGNALING PATHWAY IN AKI

NF-κB was at first found as a B-cell nuclear protein restricting to the κ enhancer of the immunoglobulin κ light chain quality (Zhang & Sun, 2015). NF-κB activation mediates two main signaling lines, namely, canonical and noncanonical pathways (Vallabhapurapu & Karin, 2009; Sun, 2010). The canonical path relies on the multisubunit inhibitors (IκBs) kinase (IKK), consisting of two catalytic subunits, IKKα and IKKβ, and a regulatory subunit named NF-κB essential modulator or IKKγ (Adli et al., 2010; Israël, 2010). Canonical signaling members of NF-κB include p50/NF-κB1, p65/RelA, and c-Rel, with the most common dimers being p50/NF-κB1-p65/RelA and p50/NF-κB1-c-Rel (White et al., 2020). In physiological conditions, NF-κB is isolated in the cytoplasm in a complex with NF-κB IκBs. When there are specific stimuli, the complex will be phosphorylated and will produce ubiquitination and degradation of the IκB, resulting in the translocation of the free NF-κB to the nucleus. In the promoter area, NF-κB will bind to a specific sequence that leads to the proinflammatory effect or encoding gene, as well as the IκB protein to restore a stable state. The heterodimer p65–p50 (NF-κB) is most commonly activated by various stimuli relevant to kidney injury, including cytokines and growth factors, pathogen-related damage, and metabolic stress (Markó et al., 2016).

Activation of NF-κB in kidney injury is caused by ischemia-reperfusion, where the kidneys are in a hypoxia condition and have low RBF. Inflammation caused by AKI is an essential factor that exacerbates kidney injury, and inflammation control is effective for minimizing kidney injury and speeding recovery (Sanz et al., 2010). Inflammation occurs starting from the activation of the signaling of various pathways that regulate the expression of pro- and anti-inflammatory mediators in tissue cells and leukocytes. These signalings have been known to come from members of the IL-1 and TNF receptor families, as well as Toll-like microbial pattern recognition receptors, which belong to the families IL-1R, IL-1, and TNFα released immediately after tissue injury or infection (Lawrence, 2009).

In in vivo studies, it has been reported that inhibition of NF-κB may result in a decrease of inflammation of the kidneys (Fujihara et al., 2007; Volpini et al., 2004). NF-κB has been known to likewise be engaged with the pathogenesis of kidney harm brought about by hypertension. A study revealed that NF-κB is a key in the regulation of kidney injury, where the findings prove that inhibition of NF-κB can weaken progressive kidney damage in rat models of hypertension and kidney injury due to aldosterone/salt (Ding et al., 2012).

Another study proved that the suppression of NF-κB in endothelial cells stops the signaling cascade leading to a decrease in kidney damage due to hypertension (Henke et al., 2007). Other studies have also reported that NF-κB activation could increase inflammation in angiotensin-II-induced mice (Müller et al., 2000). Inhibition of IKKβ expression and activation of NF-κB in ischemia-reperfusion rats with induction of renal arterial clamping has been reported, where the administration of local SIRNA IKKβ results in the inhibition of the expression of the kidney IKKβ gene, binding activity of NF-κB/DNA (Wan et al., 2011). Moreover, expanded articulation of kidney, relA, NF-κB2, and p53 qualities was confirmed in high-portion folic corrosive instigated AKI mice; results propose that NF-κB assumed a significant part in keeping up kidney work which additionally elaborates setting p53 levels during AKI (Kumar et al., 2015). Therefore, understanding the mechanism of NF-κB regulation is very important for the future state of AKI treatment.

Interestingly, a recently published work by Razak et al. (2021) revealed that the cavity of NF-κB consists of key amino acid residues, e.g., Lys244, Arg57, Ser243, Arg59, Ser249, Lys275, Gln309, and Phe310. An inhibitor of NF-κB should be able to interact with these residues either by building covalent bonds or by pi–pi interactions. Furthermore, hydrogen bonds with Gln220, Arg30, and Phe184 are also favorable to increase the affinity of the inhibitor.

PLANTS WITH NEPHROPROTECTIVE ACTIVITY: IN VITRO AND IN VIVO STUDIES

It has been proven that plants with nephroprotective activity can reduce the toxicity of drugs when both were taken together (Gaikwad et al., 2012). Nephroprotectors are compounds capable of minimizing nephrotoxic effects. Plants have nephroprotective activity, due to various complex chemical substances (Chinnappan et al., 2019). Many studies have been carried out to scientifically prove that plants can be used to treat kidney disease. Flavonoids are secondary metabolite compounds in plants that have an essential effect on kidney physiology, including nephroprotective (Vargas et al., 2018)

Flavonoids are classified as the polyphenol group. There is a benzopyrone structure in the compound, which is widely contained in various plants. This compound is the result of synthesis from the phenylpropanoid pathway (Kumar & Pandey, 2013), which has been known to have many pharmacological activities due to its antioxidant effects (Wang et al., 2018). Recent information on the impact of flavonoids on renal function and the mechanisms of action involved suggests that flavonoids have an essential effect on renal physiology and have diuretic and natriuretic properties, as well as exerting a renoprotective influence in AKI and CKD of various etiologies, including hypertension, diabetes, nephrotoxicity, and stress oxidative agents (Vargas et al., 2018).

Quercetin (Fig. 2) is classified as flavonoid compounds and generally presents as quercetin glycosides (Salehi et al., 2020). This compound has a keto carbonyl group in its molecule, and the oxygen atom on the first carbon is alkaline and can produce salts with strong acids. The molecular structure contains four active groups, i.e.,, the dihydroxyl group between ring A, o-dihydroxy group B, C ring C2, C3 double bond, and 4-carbonyl. The presence of phenolic hydroxyl groups and double bonds gives quercetin vigorous antioxidant activity (Yang et al., 2020). Quercetin effectively protects cell death induced by cisplatin, methotrexate, ciprofloxacin, NaF, HgCl₂, and cadmium (Diniz et al., 2020). The quercetin mechanism as a nephroprotective is reported to downregulate TNF-α, IL-1β, IL-6, and COX-2 by inhibiting MAPK and NF-κB pathways (Fig. 3). Also, quercetin can inhibit ROS formation in the kidneys (Liu et al., 2012). In addition, Rana et al. (2018) reported that Pb²⁺ competes with Ca²⁺ and interferes with calcium homeostasis resulting in the release of Ca²⁺ from stimulated mitochondria. This starts from the opening of the mitochondrial transition pore, resulting in total mitochondrial damage, generation of reactive species, and oxidative stress. Between cells, the proximal tubule is more susceptible to Pb-induced cellular damage, followed by apoptosis. Another study with proximal tubular cell culture from mice revealed that Pb²⁺ increases cytosol and mitochondrial calcium concentration and depletes the ER by acting on inositol 1,4,5 receptor-triphosphate (IP3Rs) (Wang et al., 2015). Ca²⁺ involvement was also demonstrated by in vitro studies on HEK293 cells. This reveals that the potential for the transient canonical TRPC1 receptor actively participates in cytotoxicity and influx of Pb²⁺ (Zhang et al., 2014).

Figure 2. Quercetin structure (PubChem CID5280343). [Click here to view]

Another test related to the anti-inflammatory effect stated that quercetin could attenuate inflammatory mediators’ production of IL-1β, IL-6, IL-8, and TNF-α LPS-induced HGF. The anti-inflammatory mechanism is through PPAR-γ activation, suppressing LPS-induced NF-κB activation (Xiong et al., 2019). Similar results revealed that quercetin was able to improve the LPS-induced inflammatory response in RAW264.7 macrophages significantly. This decreased inflammatory response through the inhibition of NF-κB, Erk1/2, and JNK signaling. The presence of hydroxy groups in flavonols has been confirmed to lead to a significant anti-inflammatory effect (Lee et al., 2018). Another result explained that quercetin has anti-inflammatory activity by inhibiting cytokine and nitric oxide synthase expression induced by inhibition of the NF-κB pathway without modifying the terminal-c-Jun N kinase activity (Comalada et al., 2005). The administration of quercetin and anticancer did not significantly affect the anticancer effects in an in vivo model using adenocarcinoma-induced mice. Proinflammatory TNF-α and intracellular mediators, such as activation of NF-κB p65 in renal tissue and iNOS expression, can be suppressed. The inhibition of renal cell apoptosis was also evaluated, where quercetin administration could suppress caspase-3 expression (Sanchez-Gonzalez et al., 2011). We conclude that there is a relationship between antioxidant and anti-inflammatory activity on the nephroprotective potency of flavonoid compounds, especially quercetin.

Combretum micranthum

In almost all West African regions, C. micranthum (CM) is usually grown wild and cultivated. This plant grows up to a height of up to 20 m or is a dense shrub (Welch et al., 2018). The leaves are used as herbal teas, trusted, and widely used in traditional medicine (Zahoui et al., 2017), including treating external wounds, malaria fever, coughs, and bronchitis (Olajide et al., 2003). The scientific results showed that CM has antimicrobial (Banfi et al., 2014; Martial et al., 2016; Udoh et al., 2012; Vroumsia et al., 2015), antityrosinase (Zeitoun et al., 2020), antihyperglycaemic (Chika & Bello, 2010; Welch et al., 2018), antihypertensive (Bourqui et al., 2020), antimalarial (Benoit et al., 1996), and anti-inflammatory activities (Olajide et al., 2003). CM aqueous extracts have more potent antioxidant activity than ethanol extracts (Touré et al., 2011). Recently, testing the antioxidant activity of hydroalcoholic extracts showed healthy antioxidant activity by scavenging AAPH, DPPH, nitric oxide, hydrogen peroxide, and chelating metal ions (Kpemissi et al., 2019).

CM nephroprotective activity has been demonstrated in in vitro, in vivo, and in silico experiments. In in vitro testing using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method using HEK-293 cells-induced cisplatin and CM (5, 10, 25, 50, 100, and 200 μg/ml), cell viability was significantly increased compared to the negative control. The EC₅₀ value was 8.136 μg/ml. In vivo nephroprotective activity was evaluated by administering CM (200 and 400 mg/kg, per oral) to mice for 10 days, followed by a single intraperitoneal CP injection on the 5th day. Administration of CM normalizes renal function at both doses by correcting markers of serum and urine renal damage, transaminases, markers of oxidative stress, and histopathological alteration in the kidneys. The in silico study showed that the docking score was higher in isovitexin and gallic acid against NF-κB and cianidanol and epicatechin against sEH (Kpemissi et al., 2019).

Figure 3. Schematic of the quercetin nephroprotective effect against various Pb-induced renal inflammation signals. [Click here to view]

Macrothelypteris oligophlebia (Bak.)

Macrothelypteris oligophlebia is distributed throughout southern China. This plant, one of the traditional Chinese herbs that have long been used to smoothen out blood circulation, removes blood stasis and dampness, edema, and inflammation (Yang et al., 2014).

Nephroprotective activity in vivo has been evaluated by a gentamicin-induction method in rats. The results revealed that extracts of M. oligophlebia at 250 and 500 mg/kg could inhibit the increased BUN and Cr levels. Additionally, activity was indicated by the influence on renal tissue enzymes, where there was a significant decrease in MDA and NO and an increase in SOD, CAT, and GSH-Px. The histopathological evaluation results showed that a dose of 500 mg/kg provides the best histological protection against the renal tubules’ damage due to gentamicin induction (Wu et al., 2012).

Table 1. The nephroprotective activity of medicinal plants. [Click here to view]

Solanum xanthocarpum

Solanum xanthocarpum is a wild herbaceous plant widespread in many places in India (Singh and Singh, 2010). Traditionally, the boiled roots are used as antipyretic, diuretic, and expectorant. Seeds are efficacious as expectorants and asthma. Whole plants and fruits are used for bronchial asthma, thymitis, intestinal disorders, hemorrhoids, and dysuria (Parmar et al., 2010). Scientific evidence proves that S. xanthocarpum has anticancer (Bhutani et al., 2010; Kumar & Pandey, 2014), antioxidant (Ghassam et al., 2014; Kumar & Pandey, 2014; Kumar et al., 2012; Nithya et al., 2018; Priya et al., 2010), anthelmintic (Priya et al., 2010), antiurolithic (Patel et al., 2012), mosquitocidal (Kumar & Murugan, 2012), antibacterial (Amin et al., 2012; Nithya et al., 2018; Priya et al., 2010), hypoglycemic (Kar et al., 2006), anti-inflammatory (Anwikar & Bhitre, 2010; More et al., 2013; Ravi et al., 2009), and hepatoprotective activities (Hussain et al., 2012; Ghassam et al., 2014; Hussain et al., 2012; Singh et al., 2015).

Table 2. In silico study: interaction between phytoconstituents and NF-κB. [Click here to view]

An in vivo study showed nephroprotective activity using gentamicin-induced mice. Extracts of S. xanthocarpum at 200 and 400 mg/kg showed protection against increased renal weight ratio. At 400 mg/kg, it provides maximum protection against the index of kidney organs and increased urine output. Also, plasma and urine test results showed a significant decrease in urea and creatinine concentrations. Evaluation of kidney antioxidants was also conducted and proved that S. xanthocarpum can prevent the decreased activity of SOD, CAT, and GSH. Interestingly, 400 mg/kg showed maximum protection, almost the same as a standard control. Histopathological observations at 200 mg/kg showed slight degenerative and necrotic tubular alteration, compared to 400 mg/kg, indicating regeneration in tubular epithelial cells (Hussain et al., 2012).

CONCLUSION

Many drugs when administered for a long period have been known for inducing AKI; however, the use of medicinal plants to prevent the damage is always interesting to be discussed, regardless of the pros and cons. Various types of plants that are often used traditionally as nephroprotective agents have been mentioned. All studies have been scientifically proven both in silico with the NF-κB regulatory approach as a signal for inflammation and in vitro and in vivo to protect the kidneys due to the induction of various nephrotoxic drugs. This review supports and confirms the usefulness of ethnomedicine, most of which have potential nephroprotective flavonoids. Most of the plants have nephroprotective-related antioxidant activity. Further research is recommended, regarding detailed efficacy and safety studies, especially on human subjects

ACKNOWLEDGMENTS

The authors thank the Rector of Universitas Padjadjaran via the Directorate of Research and Community Engagement for facilitating this study and funding the publication fee.

AUTHOR CONTRIBUTIONS

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. All the authors are eligible to be an author as per the international committee of medical journal editors (ICMJE) requirements/guidelines.

CONFLICT OF INTEREST

There are no conflicts of interest related to the publication of this paper.

ETHICAL APPROVALS

Not Applicable.

FUNDING

The publication fee is funded by the Universitas Padjadjaran Academic-Leadership Grant of Professor Dr. Jutti Levita.

PUBLISHER’S NOTE

This journal remains neutral with regard to jurisdictional claims in published institutional affiliation.

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