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  • Review Article
  • OPEN ACCESS

Tunisian Nephroprotective Plants: A Review

  • Wissem Aidi Wannes*  and
  • Moufida Saidani Tounsi
 Author information
Journal of Exploratory Research in Pharmacology   2023;8(1):74-91

doi: 10.14218/JERP.2022.00031

Abstract

In Tunisian folk medicine, several herbs are prescribed for reducing renal damage and to avoid kidney related complications. These can be of immense value in combating renal damage. In this review, we provide a description of the current literature on the use of indigenous herbs as alternative medicine for treating renal damage. The aim of this review was to collect information on promising active phytoconstituents such as organosulfur compounds, polyphenols, terpenes, alkaloids phenylpropanoids, and polysaccharides from Tunisian plants that have been scientifically examined for their nephroprotective capacities. Twenty-nine Tunisian medicinal plants have been reported for their significant nephroprotective activities against renal toxicities in animal models. Lamiaceae was the most commonly used Tunisian plant family used for renal protection. The leaves were maximally used for nephroprotection compared to the other plant parts. Nephrotoxicity is commonly the result of several nephrotoxins. Many studies have focussed on drug-caused renal failure which is one of the major problems in medical practice. Other studies focused on other important nephrotoxicity factors, including drugs and industrial chemicals. This literature review highlights the use of some medicinal plants as nephroprotective agents. To defend against this nephrotoxicity, some medicinal plants, known as nephroprotective agents, have been highlighted in this review.

Keywords

Nephroprotective effect, Kidney, Renal failure, Toxicity, Medicinal plants, Tunisia

Introduction

The kidneys are vital organs that have several physiological functions. Their principle role is to maintain homeostasis of body fluids by filtering and secreting metabolites and minerals from the blood and excreting the nitrogenous waste along with water, as urine. The kidneys also help to regulate blood pressure, glucose metabolism, and erythropoiesis.1

The kidneys filter about 180 liters of blood daily, about four times the quantity traversing any other organ. Consequently, the kidneys are highly exposed to toxins in the blood and are susceptible to tissue damage.2 Kidney disease is the ninth leading cause of death,3 and patients with kidney disease have significant morbidity and mortality.4

The number of patients presenting with kidney disorders is increasing at an alarming rate.5 Currently, there are approximately over one million people worldwide who require dialysis or a functioning graft. Kidney replacement has been the only therapy for end stage of renal failure, and dialysis has remained the only alternative when a kidney transplant is not possible.3

Nephrotoxicity is one of the most common kidney problems induced by drugs or toxins.6 A number of potent therapeutic drugs, including aminoglycoside antibiotics, chemotherapeutic agents and chemical reagents (ethylene glycol, carbon tetrachloride, and sodium oxalate), and heavy metals (lead, mercury, cadmium, and arsenic), can adversely affect the kidney resulting in acute renal failure.3 In addition to drugs, other factors can lead to acute renal failure, such as age, diabetes, hypertension, liver disease, and oliguria.5 Nephroprotective agents, such as those found in medicinal plants, have protective and curative capacities against nephrotoxicity (Fig. 1). Co-administration of various medicinal plants possessing nephroprotective activity along with different nephrotoxic agents may attenuate toxicity.7 Previously, Tunisian medicinal plants have been used to treat diabetes,8 ulcer,9 cancer10, liver,11 and coronavirus12 illnesses. In this review, we highlighted the current literature focused on Tunisian nephroprotective plants.

Tunisian medicinal plants play nephroprotective roles by inhibiting oxidative stress, apoptosis and kidney injury.
Fig. 1  Tunisian medicinal plants play nephroprotective roles by inhibiting oxidative stress, apoptosis and kidney injury.

We searched the PubMed, Scientific Information Database, Scopus, Web of Science, Science Direct, Google and Google Scholar databases for primary literature using the keywords nephroprotective effect, kidneys, nephrotoxicity, renal failure, medicinal plants, and Tunisia. A total of 175 researches were included in this work. The different experimental nephroprotectve researches allowed describing 29 Tunisian medicinal plants for their significant nephroprotective activities against renal toxicities in animal models (Table 1).13–50 These toxicities were made by several toxins belonging to drugs, industrial additives and pesticides (Table 2).14,17,20–22,24,25,28,29,31,37–43,45,47,49,51

Table 1

Tunisian medicinal plants with nephroprotective activity

Scientific plant namePart used*ExtractBioactive compoundsNephrotoxin usedReferences
Allium sativum		ClovesMethanolOrganosulfur compound (allicin)Deltamethrin13
Artemisia arborescens		LeavesAqueous ethanolPhenolic compounds (vanillic acid, coumarin, rutin, luteolin, naringenin and quercetin)Estradiol + progesterone14
Artemisia campestris		Aerial partsEssential oilTerpenes (β-pinene, p-cymene and α-pinene)Deltamethrin15
Chlorpyrifos16
Capparis spinosa		LeavesMethanolPhenolic compounds (rutin, resveratrol, coumarin, luteolin and epicatechin)Cisplatin17
Ceratonia siliqua		LeavesEthyl acetatePhenolic compounds (syringic acid, myricetin glycosides and gallic acid derivatives)CCl418
Citrus limon		LeavesEssential oilTerpene (limonene)Aspirin19
Eryngium maritimum		SeedsMethanolPhenolic compounds (caffeic acid, protocatechuic acid gallic acid, luteolin and kaempferol)Cisplatin20
Eucalyptus globulus		LeavesAqueousPhenolic compounds (rutin, ellagic acid, chlorogenic acid, and quercetin 3-glucuronide)Acetaminophen21
Euphorbia bivonae		LeavesPolysaccharidesMonosaccharides (saccharose, arabinose, inositol, glucose, pyranose, trehalose and fructose)Hydrogen peroxide22
Globularia alypum		LeavesMethanolPhenolic compound (globularin)Deltamethrin23
Hammada scoparia		LeavesMethanolAlkaloids (carnegine and N-methylisosalsoline) and flavonoids (isorhamnetin triglycerides)Ethanol24
Hyparrhenia hirta		Aerial partsMethanolFlavonoid compounds (apigenin, quercetin and luteolin)Sodium nitrate25
Lavandula stoechas		Aerial partsEssential oilTerpenes (tricyclene, cymene, Δ-Cadinene and Selina-3,7(11)-diene)Malathion26
Lycium europaeum		LeavesMethanolPhenolic compounds (cisplatin, caffeic acid, gallic acid, naringenin, epicatechin, vanillic acid, rutin and p-coumaric acid) PolysaccharideCCl427
PolysaccharideCisplatin28
Malva sylvestris		Flowers LeavesAqueousPhenolic compounds (gallic acid, p-coumaric acid, vanillic acid, rutin, kaempferol, quercetin and luteolin)Vanadium29
MethanolLithium carbonate30
Mentha piperita		LeavesEssential oilTerpenes (menthol and iso-menthone)CCl431
Morus alba		LeavesAqueous acetonePhenolic compounds (chlorogenic acid and its derivatives)Glyphosate32
Nitraria retusa		FruitsAqueousPhenolic compounds (chlorogenic acid, p-coumaric acid, caffeic acid, gallic acid and kaempferol)Penconazole33
Olea europea		FruitsOilPhenolic compounds (oleuropein and hydroxytyrosol)Acrylamide34
LeavesAqueousDeltamethrin35
FruitsEthanolBisphenol A36
Diclofenac37
Opuntia ficus-indica		CladodesAqueousPhenolic compounds quercetin, vanillic acid, gallic acid, rutin, kaempferol, catechin, epicatechin, coumarin, isorhamnetin and caffeic acid)Lithium carbonate38
Sodium dichromate39
Periploca angustifolia		LeavesPolysaccharidesMonosaccharides (saccharose, trehalose, L-inositol and M-inositol)Cadmium40
Phoenix dactylifera		FruitsAqueousPhenolic acids (ferulic, caffeic and p-coumaric acids)Dichloroacetic acid41
Pinus halepensis		NeedlesEssential oilTerpenes (Z-β-caryophyllene, β-myrcene and α-pinene)Aspirin42
Rhus tripartitum		FruitsMethanolPhenolic acid (betulinic acid)Cisplatin43
Rosmarinus officinalis		LeavesAqueousPhenolic compounds (carnosic and rosmarinic acids)CCl444
Salvia officinalis		Aerial partsEssential oilTerpenes (β-caryophyllene, limonene and carvacrol)Vanadium45
Teucrium polium		Aerial partsAqueousphenylpropanoid glycosides (verbascoside and poliumoside), flavones (apigenin and its derivatives) and two methoxyflavonesCCl446
Trigonella foenum-graecum		SeedsPowderFlavonoid glycosides (vicenin-2, isoschaftoside and isoorientin)Aluminum chloride47
CCl448
Vitis vinifera		Seeds/SkinEthanolPhenolic compounds (2,5-dihydroxybenzoïc acid gallic acid, and vanillin)Doxorubicin49
FruitsPowderOxidative stress50

*Sientific plant names were followed by references. CCl4, carbon tetrachloride.

Table 2

Effect of Tunisian medicinal plants on different nephrotoxins

Nephrotoxicity factorsModel nephrotoxin usedScientific plant name*
PesticidesDeltamethrinAllium sativum13; Artemisia campestris15; Globularia alypum23; Olea europea35
ChlorpyrifosArtemisia campestris16
MalathionLavandula stoechas26
GlyphosateMorus alba32
PenconazoleNitraria retusa33
AcrylamideOlea europea34
CCl4Ceratonia siliqua18; Lycium europaeum27; Mentha peperita31; Rosmarinus officinalis44; Teucrium polium46; Trigonella foenum-graecum48
Industrial additivesBisphenol AOlea europea36
Hydrogen peroxydeEuphorbia bivonae22
Cadmium SodiumPeriploca angustifolia40
dichromateOpuntia ficus-indica39
Sodium nitrateHyparrhenia hirta25
VanadiumMalva sylvestris29; Salvia officinalis45
DrugsDichloroacetic acidPhoenix dactylifera41
DoxorubicinVitis vinifera49
AcetomophenEucalyptus globules21
Aluminum chlorideTrigonella foenum-graecum47
AspirinCitrus limon51; Pinus halepensis42
CisplatinCapparis spinosa17; Eryngium maritimum20; Lycium europaeum28; Rhus tripartitum43
DiclofenacOlea europea37
EstradiolArtemisia arborescens14
EthanolHammada scoparia24
Lithium carbonateOpuntia ficus-indica38; Malva sylvestris31
ProgesteroneArtemisia arborescens14

CCl4, carbon tetrachloride.

Allium sativum

Allium sativum belongs to the family of Alliaceae, popularly known as garlic. It has reported anti-atherosclerotic, cardioprotective, neuroprotective, antihyperlipidemic, antidiabetic, antihypertension, antistress, anticancer, antiviral, antibacterial, antifungal, anti-oxidant, and dermatologic properties.52 Ncir et al.13 determined that the nephroprotective potential of the methanol extract from A. sativum cloves (20 mg/kg body weight (BW) against deltamethrin (7.2 mg/kg BW) caused oxidative damage in rat kidneys. Deltamethrin treatment increased kidney conjugated dienes and lipid peroxidase (LPO) levels. However, catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels were decreased. Garlic administration regulated these changes provoked by deltamethrin. Allicin is one of the major bioactive components of garlic constituted from the stable precursor allicin by the enzyme action alliinase when garlic cloves are crushed or macerated. García Trejo et al.53 determined that allicin had beneficial effects in chronic kidney disease compared to Losartan.

Artemisia arborescens

Artemisia arborescens is a perennial evergreen woody shrub belonging to the family of Asteraceae.54A. arborescens is a widely used traditional medicine that possesses ethnomedical and biological benefits.55 The beneficial effects of the aqueous ethanol extract from A. arborscens leaves (200 mg/kg BW) were studied against oestroprogestative-induced (35 mg/kg of estradiol and 125 mg/kg of progesterone, BW) kidney damage in rats. A. arborescens extract was found to optimize many parameters of oestroprogestative toxicity.14 The protective effect of A. arborescens was mainly attributed to the presence of phenolic acids and flavonoids. A. arborescens is rich in catechic acid, caffeic acid, epicatechic acid, vanillic acid, naringenin, coumarin, cinamic acid, quercetin, rutin, luteolin, kaempferol, and isorhamnetin. Among these phenolics, the potent nephroprotective effect of vanillic acid,56 coumarin,57 rutin,58 and luteolin59 was determined against cisplatin-induced nephrotoxicity in rats. Additionally, the renal protective potential of naringeninn60 and quercetin61 was studied in cadmium-induced oxidative renal dysfunction in rats.

Artemisia campestris

Artemisia campestris is a perennial herb belonging to the family of Asteraceae. A. campestris has many medicinal actions including anthelmintic, antidiabetic, anticancer, antimicrobial, antifungal, antihypertensive, emmenagogue, and antivenom. It has been also used to treat cutaneous, genital, digestive, and respiratory disorders.62 Saoudi et al.15 investigated the protective effects of A. campestris essential oil against deltamethrin nephrotoxicity in rats. Deltamethrin toxicity caused a significant increase in creatinine, urea, and uric acid levels, and a decrease in LPO, SOD, CAT and GPx. However, A. campestris essential oil reduced the deltamethrin-induced alterations in serum levels, lipid peroxidation, and oxidative stress. The protective effect of A. campestris essential oil could be attributed to its anti-oxidant potential. Similar results were obtained by Saoudi et al.16 who determined the protective effect of A. campestris essential oil against chlorpyrifos-induced kidney injury in rats. Akrout et al.63 found that A. campestris essential oil was dominated by β-pinene, p-cymene, and α-pinene. In fact, Başar64 reported that pinenes in volatile oils derived from plants are used widely to treat renal stone disease.

Capparis spinosa

Capparis spinosa is a spontaneous xerophyte plant belonging to Capparaceae family, widely found in the Mediterranean. C. spinosa is popularly used as a condiment65 and medicinal plant.66 It is used in traditional medicine to treat diseases such as gastrointestinal problems, hypertension, anemia,67 rheumatism,68 and diabetes.69 It is also an analgesic, anti-arthritic,70 antihemorrhoidal, anticancer,71 anti-inflammatory,72 depurative, diuretic,73 emmenagogue, and anti-oxidant.74 The nephroprotective action of the methanolic C. spinosa (200 mg/kg in olive oil) was determined against cisplatin-provoked (13 mg/kg in olive oil) kidney injury in rats. Pre-treatment with the methanolic extract of C. spinosa leaves 7 days before cisplatin exposure and daily thereafter significantly reduced plasma levels of creatinine, urea, and uric acid, reduced malondialdehyde (MDA) levels, and reduced anti-oxidant enzyme activity of SOD, CAT, and GPx in the kidney and reversed the kidney damage.17 The leaf of this plant is rich in rutin, resveratrol, coumarin, epicatechin, and luteolin,73 all of which have been shown to demonstrate protection against cisplatin-induced nephrotoxicity in rats, as reported by Radwan and Fattah58 for rutin, Valentovic et al.75 for resveratrol, Sen et al.57 for coumarin, Tanabe et al.76 for epicatechin, and Domitrović et al.59 for luteolin.

Ceratonia siliqua

Ceratonia siliqua is a slow-growth ever-green tree belonging to the Leguminosae family, cultivated for years in the Mediterranean region. C. siliqua fruits, brown pods 10–25 cm in length, have traditionally been used as animal and human food. The seed is mainly used for gum extraction. C. siliqua pods, bark, and leaves have been used in Tunisian folk medicine as a laxative, diuretic, antidiarrheal, and to treat gastroenteritis of lactating babies.77 Animals received the ethyl acetate extract of C. siliqua leaves (250 mg/kg BW) daily by intraperitoneal injection for 8 days followed by a single dose of CCl4 (1 ml/kg in olive oil) using an intragastric tube after 24 hours of the last dose showed increased levels of urea, creatinine, and LPO with a concomitant decrease in SOD, CAT, and GPx in the kidney. Pretreatment with ethyl acetate extract of C. siliqua leaves had a potent nephroprotective effect in accordance with histopathological observations. The leaf extract of this plant mainly contains syringic acid, myricetin glycosides, and gallic acid derivatives.18 Sancak et al.78 noted the potent protective effect of syringic acid on kidney ischemia-reperfusion injury. The beneficial effect of myricetin on renal function was reported by Ozcan et al,79 and Asci et al.80 determined the beneficial impact of gallic acid against methotrexate-induced kidney injury in rats.

Citrus limon

Citrus limon is a medicinal plant of the family Rutaceae found in Tunisia and other Mediterranean countries (Egypt, Italy, Spain and Turkey).81C. limon has been used in folk medicine to treat obesity, diabetes, high lipid, cardiovascular diseases, brain disorders, and some cancer types.51C. limon leaf essential oil (1 ml/kg) was evaluated for its nephroprotective effect against a high dose of aspirin-induced acute kidney damage (600 mg/kg) in rats. C. limon essential oil protected against aspirin, showing a decrease in thiobarbituric acid reactive substances (TBARS) and an increase in SOD, CAT, and GPx.82 Limonene is the main component of C. limon essential oil fruits,82 leaves,83 and peels.84 Rehman et al.85 reported the protective role of limonene against doxorubicin-induced renal damage in the treatment of cancer.

Eryngium maritimum

Eryngium maritimum is a perennial herbaceous halophyte plant belonging to the Apiaceae family, which is widely distributed in dunes and sandy beaches of several Mediterranean countries and the Black Sea, Atlantic, and Baltic coasts. It has been introduced into parts of eastern North America and Australia.86E. maritimum has numerous folk medicinal uses including as a diuretic, kidney stone inhibitor, aphrodisiac, expectorant, anthelmintic, and antitoxin against various infections.87 Increases in serum levels of creatinine, urea, and uric acid caused by cisplatin (13 mg/kg in corn oil) were restored by methanolic E. maritimum seed extract (150 mg/kg in corn oil), accompanied by an increase in CAT, SOD and GPx.20 Mejri et al.20 reported that this seed extract was rich in caffeic acid, gallic acid, protocatechuic acid, kaempferol, and luteolin. Matboli et al.88 explained the curative potential of caffeic acid against diabetic kidney disease, and Nabavi et al.89 showed that gallic acid isolated from Peltiphyllum peltatum had nephroprotective activity against sodium fluoride-induced kidney damage. Protocatechuic acid was found as a protective agent against cadmium-induced toxicity in the kidney and liver.90 Vijayaprakash et al.91 showed that kaempferol had significant nephroprotective potential against mercuric chloride-induced nephrotoxicity in rats. Luteolin was also found to be effective against cisplatin-induced nephrotoxicity in mice .59

Eucalyptus globulus

Eucalyptus globulus is a very common tree throughout the world belonging to the Myrtaceae family. Its leaves, bark, and fruit have been traditionally used as remedies to treat inflammation and promote wound healing.92E. globules treatment has been shown to effectively protect against acetaminophen-provoked nephrotoxicity in mice by restoring SOD, CAT, and GPx levels. The nutraceutical advantage of E. globulus extract is attributed to its flavonoid, flavonol, and phenolic compounds.21 Ferreira et al.93 found that E. globulus leaves were rich in rutin, ellagic acid derivatives, quercetin 3-glucuronide, and chlorogenic acid, which have all been investigated for their nephroprotective effects.58,94–96

Euphorbia bivonae

Euphorbia bivonae is an herbaceous plant belonging to the Euphorbiaceae family and is widespread in the coastal areas of the Mediterranean basin.97E. bivonae has several biological properties, including antiproliferative,98 anti-oxidant, nephroprotective,22 and hepatoprotective99 effects. Athmouni et al.22 evaluated the preventive action of E. bivonae leaf polysaccharides against hydrogen peroxide (H2O2)-induced toxicity in human embryonic kidney (HEK293) cells. Results revealed that H2O2-exposure induced a significant increase in intracellular reactive oxygen species and lipid peroxidation in HEK293 cells. However, E. bivonae polysaccharide pretreated cells (100 µg/mL) significantly enhanced the anti-oxidant status (SOD, CAT, GPx, and GSH) of HEK293 cells that were decreased after H2O2 exposure. Accordingly, the HEK293 cells pretreated with E. bivonae polysaccharide compounds had enhanced cell viability following H2O2 exposure. Polysaccharide analysis showed the richness of E. bivonae in seven monosaccharides: saccharose, arabinose, inositol, glucose, pyranose, trehalose, and fructose.

Globularia alubum

Globularia alubum is a perennial shrub plant belonging to the Globulariaceae family, widely distributed in the Mediterranean area and largely used for its therapeutic virtues.100G. alubum species are known for their medicinal properties.101G. alypum is commonly used as a hypoglycaemic, laxative, cholagogue, stomachic, and purgative agent, as well as in the treatment of renal disease.23 The protective effect of methanol extract from G. alypum leaves (400 mg/kg in corn oil) against the nephrotoxicity induced by a chronic exposure to deltamethrin (4 mg/kg in corn oil) has been studied in rats. Deltamethrin administration provoked kidney damage, and treatment with G. alypum leaf extract restored plasma creatinine, urea, and uric acid levels and reduced the elevated MDA and PC levels. G. alypum leaf extract has been shown to restore renal activity in accordance with histopathological observations owing to its bioactive compounds.102G. alypum leaf extract is rich mainly in globularin (60.31%). Merghache et al.103 isolated this phenolic compound and determined its antidiabetic and antilipidemic capacities in normal and streptozotocin-induced diabetic rats.

Hammada scoparia

Hammada scoparia is a small highly-branched halophytic shrub belonging to the Chenopodiaceae family. It is widely used in North African traditional medicine to prevent several diseases such cancer, hepatitis, inflammation, and obesity. The methanol extract of H. scoparia leaves (200 mg/kg/day) was evaluated for its renoprotective effect against ethanol-induced (4 g/kg) renal dysfunction in rats. H. scoparia extract attenuated the increase of TBARS in kidneys, and enhanced the anti-oxidant status of rats by increasing the levels of SOD, CAT, and GPx. The overexpression of glycogen synthase kinase–3β and proline–rich tyrosine kinase 2 in kidneys of ethanol–treated rats was normalized after H. scoparia extract treatment.24H. scoparia leaf extract is rich in alkaloids (carnegine and N-methylisosalsoline) and flavonoids (isorhamnetin triglycerides), as reported by Bourogaa et al.104 and Ben Salah et al.105 Qiu et al.106 determined the potential renoprotective effects of isorhamnetin in a type 2 diabetic rat model.

Hyparrhenia hirta

Hyparrhenia hirta is a perennial grass belonging to the Poaceae family. It is native to the southern Africa and Mediterranean regions.107H. hirta is used in traditional medicine for its diuretic properties.108 Bouaziz et al.25 studied the nephroprotective effect of methanolic extract from H. hirta aerial parts (200 mg/kg in corn oil) against sodium nitrate-induced kidney (400 mg/kg in corn oil) dysfunction. Sodium nitrate-mediated oxidative stress in kidneys is characterized by enhanced lipid peroxidation and reduced CAT, SOD, and GPx activity. Renal damage was histologically characterized by degeneration of renal tubule cells and mononuclear cell infiltration. A reversal of anti-oxidant enzymes and peroxidative damage in kidneys by H. hirta extract has been attributed to its anti-oxidant and antiperoxidative properties and its role as a scavenger of free radicals, which could be due to its flavonoid content, namely apigenin, quercetin, and luteolin derivatives.109 The potent nephroprotective effect of apigenin,110 quercetin,111 and luteolin59 was determined against cisplatin-induced nephrotoxicity in rats.

Lavandula stoechas

Lavandula stoechas is a medicinal plant belonging to the Lamiaceae family.112 Selmi et al.26 investigated the nephroprotective activity of L. stoechas aerial part essential oil (10, 30, and 50 mg/kg) against malathion-induced (200 mg/kg) oxidative stress in mice. Malathion treatment decreased body weight and perturbated metabolic parameters. However, L. stoechas essential oil abolished all malathion-induced body gain loss and kidney relative weight increase, hemodynamic, and metabolic disorders, as well as renal oxidative stress.26 The chemical composition of L. stoechas essential oil is characterized by the presence of d-fenchone, α-pinene, camphor, camphene, Eucapur, limonene, linalool, and endobornyl acetate. The essential oils also contain smaller percentages of tricyclene, cymene, Δ-cadinene, and selina-3,7(11)-diene.113 These molecules are the prime anti-oxidant source of this plant, and underlie its ability to scavenge free radicals, which are the major cause of lipid peroxidation.114

Lycium europaeum

L. europaeum is a spiny shrub belonging to the Solonaceae Family and is dispersed throughout all countries in the Mediterranean basin.115 It has been used in numerous traditional remedies for skin burning, rheumatic pain, constipation, hypertension, infectious ailments, and kidney and liver disorders.116 Cisplatin treatment has been shown to significantly augment serum levels of urea, creatinine, uric acid, and blood urea nitrogen in mice. L. europaeum leaf polysaccharide has been shown to reduce these renal biochemical parameters. Similar results were observed for the methanol extract from L. europaeum leaves on kidney injury induced by cisplatin27 and by CCl4.28L. europaeum leaf extract is rich in caffeic acid, gallic acid, naringenin, epicatechin, vanillic acid, rutin, and coumaric acid. Its nephroprotective activity against cisplatin has been attributed to caffeic acid phenethyl ester,117 gallic acid,118 naringenin,60 epicatechin,76 vanillic acid,56 rutin,58 and p-coumaric acid.119

Malva sylvestris

Malva sylvestris is a common mallow belonging to the Malvaceae family. This plant is native to Europe, Asia, and North Africa, and its medicinal applications include its use as a diuretic, laxative, spasmolytic, lenitive, and choleretic. Malva sylvestris is also used as bronchodilator, expectorant, antitussive, and antidiarrheal, and has been highly recommended for acne and skin care, and as an antiseptic, emollient, and demulcent.120 The decoction of M. sylvestris leaves and flowers was investigated for its nephroprotective action against vanadium-induced kidney damage in rats.29 For 90 days, rats were given 0.2 g dw/kg BW of M. sylvestris decoction and 0.24 mmol/kg BW of vanadium in drinking water. Results showed that vanadium poisoning resulted in a significant increase in the formation of free radicals and anti-oxidant enzymes (SOD, CAT, and GPX) in the kidney. However, treatment with M. sylvestris decoction restored lipid peroxidation levels, anti-oxidant enzyme activities, and histological features, which appeared normal compared to control rats. The beneficial effects of M. sylvestris leaf extract (0.2 g/kg) were also observed against lithium carbonate-induced (25 mg/kg) renal damage in rats.30 As reported by Ben Saad et al.30 the protective properties of M. sylvestris extract could be related to its rich make-up of phenolic acids (epicatechic acid, gallic acid, coumaric acid, vanillic acid, and catechic acid) and flavonoids (rutin, kaempferol, quercetin, and luteolin). In fact, potent nephroprotective effects of gallic acid,118p-coumaric acid,119 vanillic acid,56 rutin,58 kaempferol,91 quercetin,61 and luteolin59 were found against several kidney toxicities in rats.

Mentha peperita

Mentha peperita is a native genus of the Mediterranean region belonging to the Lamiaceae family. It is widely used in food and in traditional medicine.121 Bellassoued et al.31 investigated M. peperita leaf essential oil for its nephroprotective action against CCl4-induced renal failure in rats. M. peperita leaf essential oil was orally administrated for 7 consecutive days (5, 15, 40 mg/kg BW) to rats prior to CCl4 (1 ml/kg BW) intraperitoneal treatment. Results showed that pretreatment with M. peperita leaf essential oil at 15 and 40 mg/kg prior to CCl4 significantly reduced stress parameters (urea and creatinine). A significant reduction in kidney lipid peroxidation (TBARS) and an increase in anti-oxidant enzymes (SOD, CAT, and GPx) were also observed after treatment with M. peperita leaf essential oil (40 mg/kg) compared to CCl4-treated rats. Furthermore, pretreatment with M. peperita leaf essential oil at 40 mg/kg markedly ameliorated the histopathological hepatic and kidney lesions induced by CCl4. M. peperita leaf essential oil contains active ingredients including menthol and iso-menthone. These two compounds exhibit a potent anti-inflammatory activity,121 indicating that M. peperita leaf essential oil could be a promising natural product against CCl4-induced oxidative damage in the kidney, consistent with that reported by Bellassoued et al.31

Morus alba

The leaves of M. alba of the Moraceae family, commonly known as mulberry, are mainly used as food for silk worms and are sometimes used as cattle fodder in different parts of the world.122 The infusion and decoction of leaves have been used to prevent or treat urinary disorders.123 The aqueous acetonic extract of M. alba leaves (100 mg/kg) was studied against glyphosate-induced (100 mg/kg) kidney injury in mice.32 Renal oxidative stress induced by glyphosate was evidenced by an increase in MDA and protein carbonyl levels and a decline in SOD activity. M. alba leaf extract appeared to modulate these altered biochemical parametres by maintaining free iron and Ca2+ homeostasis, as well as regulating endogenous anti-oxidant enzymes. The aqueous acetonic fraction of M. alba leaves is rich in chlorogenic acid and its isomers,32 which can protect kidneys from glyphosate-induced nephrotoxicity.96

Nitraria retusa

Nitraria retusa belongs to the Nitrariaceae family and is used for its anti-inflammatory properties124 and to facilitate healing.125 In this study, the nephroprotective effect of aqueous extract from N. retusa fruit (300 mg/kg BW) against penconazole (67 mg/kg BW) caused kidney injury.33N. retusa treatment provoked a significant decrease in the levels of MDA, H2O2, protein carbonyl and advanced oxidation protein products, as well as improved alkaline phosphatase (ALP) and gamma glutamyltranspeptidase activities. Polyphenol constituents of N. retusa fruit aqueous extract could enhance their anti-oxidant activities in nephroprotection. N. retusa fruit extract mainly contains hydroxycaffeic acid, epicatechin derivatives, p-coumaric acid, cyanidin derivative, 3-O-methylgallic acid, taxifoline, chlorogenic acid, and kaempferol derivative. Among these phenolics, chlorogenic acid,96p-coumaric acid,119 caffeic acid,88 gallic acid,118 and kaempferol91 are known for their potent nephroprotection.

Olea europea

Olea europea is a known olive tree belonging to the Oleaceae family. It represents a great economic and social importance owing mainly to the great value of olive oil. This olive oil is the primary source of fat in the Mediterranean diet, which has been associated with low mortality related to cardiovascular disease.126 Ghorbel et al.34 found that extra vierge olive oil abrogated acrylamide-induced nephrotoxicity. Ethanolic extract from O. europea fruit (200 mg/kg BW) and its phenolic compound, oleuropein (50 mg/kg BW), has been shown to protect against nephrotoxicity caused by deltamethrin (15 mg/kg bw) in rats.35 Deltamethrin administration can increase MDA levels and reduce SOD and CAT activities. O. europea fruit and oleuropein have been used as treatments for inflammation and apoptosis. Oleuropein, verbascoside, luteolin-7-glucoside, apigenin-7-glucoside, and hydroxytyrosol are the main components of the ethanolic extract from O. europea fruit.35 The nephroprotective effect of oleuropein and hydroxytyrosol extracted from Tunisian olive leaf extract have been investigated in rats treated with bisphenol A.36 In a recent study, Soussi et al.37 found that the aqueous extract of Tunisian O. europaea leaves protected against kidney damage induced by diclofenac in mice.

Opuntia ficus-indica

Opuntia ficus-indica is a plant popularly known as prickly pear belonging to the Cactaceae family. It is widely distributed in the Mediterranean area, Mexico, and South Africa, and is widely known because of its nutritional and medicinal usage.127 Administration of lithium carbonate (25 mg/kg BW) has been shown to cause a significant increase in serum creatinine, uric acid, and urea levels. Additionally, a significant decrease in SOD, CAT, and GPx activities was associated with a significant increase in MDA levels. However, treatment with O. ficus indica extract (100 mg/kg BW) prevented these alterations and maintained the anti-oxidant status in rats. Histopathological observations support this biochemical evidence of nephroprotection.38 Similar results were obtained for the aqueous extract from O. ficus-indica cladodes on kidney injury induced by sodium dichromate.39 As reported by Saad et al.,38 the aqueous extract from O. ficus-indica cladodes was characterized by the presence of quercetin, vanillic acid, gallic acid, rutin, kampferol, catechin, epicatechin, coumarin, isorhamnetin, and caffeic acid. All of these phenolic compounds have been well studied for their potent nephroprotection, particularly quercetin,61 vanillic acid,56 gallic acid,118 rutin,58 kaempferol,91 catechin,128 epicatechin,65 coumarin,57 isorhamnetin,106 and caffeic acid.88

Periploca angustifolia

Periploca angustifolia evergreen shrub is a member of the Apocynaceae family. It is found wild in North Africa (from Morocco to Egypt), southern Spain, Sicily, Malta, Crete, Lebanon, and Syria. P. angustifolia is used in traditional medicine for diabetes, rheumatism, hemorrhoids, and gastric ulcer.129 The preventitive action of polysaccharides isolated from P. angustifolia leaves against cadmium-caused oxidative stress in kidneys of rats has been tested. Results indicated that cadmium treatment increased the levels of urea and creatinine in the serum. The increased levels of protein oxidation and lipid peroxidation along with decreased activities of SOD, CAT and GPx were ameliorated by P. angustifolia polysaccharides pre-treatment. Histopathological studies also supported the prevention action of P. angustifolia polysaccharides. Saccharose is the major monosaccharide component of P. angustifolia leaves, followed by trehalose, L-inositol, and M-inositol, as reported by Athmouni et al.40

Phoenix dactylifera

Phoenix dactylifera is a tree commonly known as date palm belonging to the Arecaceae family. P. dactylifera is mostly cultivated for the consumption of its fruit, which has been utilized since ancient times as an important staple food and in ethnomedicine in different parts of the world.130 The fruit of P. dactylifera is used as a detersive and astringent for intestinal ailments, treatment for sore throat, colds, bronchial asthma, to relieve fever, cystisis, gonorrhea, edema, liver and abdominal ailments, and to counteract alcohol intoxication.131 Dichloroacetic acid administration (2 g/l) caused augmentation of renal MDA levels and significant diminution of GSH levels. Moreover, dichloroacetic acid altered the anti-oxidant enzyme activities and deteriorated renal function, as assessed by increased plasma urea, uric acid, and creatinine levels. Treatment with P. dactylifera extract (4 ml/kg) significantly normalized the plasma levels of creatinine, urea, and uric acid, reduced the MDA levels, significantly normalized anti-oxidant enzyme activities and GSH levels, and restored the kidney histology in rats.41 Therefore, it has been speculated that P. dactylifera extract protects rats from kidney damage through its anti-oxidant capacity attributed to make-up of phenolic acids, mainly ferulic, caffeic, and p-coumaric acids.41 In fact, ferulic,132 caffeic,88 and p-coumaric119 acids are known for their efficient nephroprotective action.

Pinus halepensis

Pinus halepensis is a tree belonging to the Pinaceae family found around the Mediterranean basin. The resin and decoction of all Pinus species have antiseptic, diuretic, rubefacient, vermifuge, antidiabetic, and cicatrisant properties.133 Bouzenna et al.42 studied the protective effect of essential oil from P. halepensis needles on aspirin-induced acute kidney damage in rats. Rats were orally treated with P. halepensis essential oil (1 ml/kg) for 56 days and then given aspirin (600 mg/kg) orally thrice a day at an interval of 4 h for 4 successive days. Results showed that aspirin induced an increase in serum biochemical parameters as well as oxidative stress in kidney. There was an increase in TBARS and a decrease in SOD, CAT, and GPx in kidney. Administration of P. halepensis essential oil corrected these parameters. Hamrouni et al.134 found that the essential oil of Tunisian P. halepensis needles was characterized by the predominance of monoterpene hydrocarbons, mainly β-caryophyllene, β-myrcene and α-pinene. These volatile compounds could interact to protect against aspirin-induced nephrotoxicity.

Rhus tripartitum

Rhus tripartitum is a dioecious shrub belonging to the Anacardiaceae family.135R. tripartitum is widely used to treat many diseases such as diarrhea and dysentery, colitis, gastointestinal diseases, inflammatory diseases, diabetes, haemoptysis, conjunctivitis, animal bites and poisons, hemorrhoids, sexual disease, fever, pain, and various cancers. Tlili et al.43 investigated the protective action of methanolic extract from R. tripartitum fruit (200 mg/kg in olive oil) against cisplatin-induced (13 mg/kg) nephrotoxicty in rats. The increased levels of biochemical parameters (creatinine, urea, and uric acid) were attenuated by pretreatment with R. tripartitum fruit extract. Histopathologic observation showed that pretreatment with R. tripartitum fruit extract restored the pathology. These results could be due to the richness of R. tripartitum fruit extract in phenolics, especially betulinic acid. In fact, the efficient renoprotective effects of betulinic acid isolated from Cornus walteri in cisplatin-provoked renal toxicity were determined by Lee et al.136

Rosmarinus officinalis

Rosmarinus officinalis, commonly known as rosemary is a perennial, aromatic medicinal plant belonging to the Lamiaceae family. It is shrub-shaped with branches full of leaves, exuding a characteristic fragrance.137 One study evaluates the effects of aqueous extract from R. officinalis leaves against kidney toxicity induced by CCl4 in mice. Results showed that the renal damage induced by CCl4 was associated with a rise in oxidative stress, an increase of TBARS, and changes the nephropathology parameters including creatinine, blood urea nitrogen, and urea. However, a decrease in GSH levels and anti-oxidant enzymes (SOD, CAT, and GPx) was observed. These findings were substantiated by histological analysis. Pretreatment with R. officinalis leaf extract attenuated CCl4-related toxic effects.44 The polyphenolic profile of Tunisian R. officinalis leaf extract is characterized by its richness in carnosic and rosmarinic acids.138 The potent nephroprotective effects of carnosic139 and rosmarinic140 acids were observed in cisplatin-induced nephrotoxicity in rats.

Salvia officinalis

Salvia officinalis, popularly known as sage, is a member of the Lamiaceae family. It is an aromatic plant widely distributed in the world. Since ancient times, S. officinalis has been an ingredient in perfumes, a flavoring in a variety of food preparations,141 and a medicinal plant used to fight fever, rheumatism, perspiration, sexual malfunction, chronic bronchitis, and various mental diseases.142 Koubaa et al.45 evaluated the impact of the essential oil from S. officinalis aerial parts (15 mg/kgBW) on renal nephrotoxicity induced by vanadium (5 mg/kg BW) in rats. A marked increase in LPO and PCO levels with a significant decrease in SOD, CAT, and GPx. However, the administration of S. officinalis essential oil significantly restored these biochemical markers and pathological lesions. This protective effect seems to be due to the richness of S. officinalis essential oil in β-caryophyllene, limonene, carvacrol, caryophyllene, borneol, α-pinene, and α-thujene, as reported by Koubaa et al.45 Horváth et al.143 found that β-caryophyllene ameliorated cisplatin-induced nephrotoxicity. Rehman et al.85 reported the protective role of limonene against renal damage induced by the anticancer drug doxorubicin. The protective effect of carvacrol on renal function in gentamicin-induced nephrotoxicity in rats was determined by Ahmadvand et al.144

Teucrium polium

Teucrium polium is defined as golden germander belonging to the Lamiaceae family. It has been used to treat abdominal pain, indigestion, and diabetes. The aqueous extract of T. polium aerial parts (5 g/l) was investigated against CCl4-induced (0.5 ml/kg) nephrotoxicity in rats. CCl4 treatment increase serum renal markers (urea and creatinine) and lipid peroxidation and decreased anti-oxidant enzymes (SOD, CAT and GPx). However, pretreatment with T. polium extract protected against oxidative damage and biochemical changes induced by CCl4, which were validated by histopathological observations.46 According to Goulas et al.,145T. polium aerial part extract is characterized by the presence of phenylpropanoid glycosides (verbascoside and poliumoside), flavones (apigenin and its derivatives), and two methoxyflavones, with poliumoside being the most abundant and active component of T. polium extract.

Trigonella foenum-graecum

Trigonella foenum-graecum is an annual herb popularly known as fenugreek that belongs to the Leguminosae family. It is native to an area extending from Iran to northern India and widely cultivated in China, India, Egypt, Ethiopia, Morocco, Ukraine, Greece, and Turkey.146 It is an ancient traditional medicinal plant147 due to its olfactory, antifever, anti-inflammatory, antimicrobial, anticancer, antidiabetic, antihyperglycemic, laxative, galactogogue, and digestive effects. Belaïd-Nouira et al.47 evaluated fenugreek seeds (5% in the diet) for their effects on rat nephrotoxicity caused by aluminum chloride (500 mg/kg BW for one month then 1,600 ppm via drinking water). Aluminum chloride inhibited ALP, decreased total antioxidant status, and an induced LPO in the blood and brain. Treatment with fenugreek seed powder helped to restore normal plasma values of urea, creatinine, ALP, and glucose, as well as increased the total antioxidant status, inhibited LPO, and alleviated histopathological changes in the injured kidney. Belguith-Hadrich et al.148 also determined the potent renoprotective action of fenugreek seeds on renal oxidative stress and nephropathy caused by a high cholesterol diet in rats. Mbarki et al.48 noted that fenugreek seed supplementation protected the kidney from CCl4-induced oxidative stress and toxicity in rats. According to Belaïd-Nouira et al,47 Belguith-Hadrich et al,148 and Mbarki et al,48 the anti-oxidant activity of fenugreek seeds could be attributed to polyphenols, particularly flavonoids. Three flavonoid glycosides were detected in methanol extract from the fenugreek seed extract: vicenin-2, isoschaftoside, and isoorientin.149

Vitis vinifera

Vitis vinifera is a perennial, woody climbing grapevine belonging to the Vitaceae family. It is indigenous to southern Europe and western Asia and is cultivated today in all temperature regions of the world.150 Grape seeds contain 6–20% oil, used for edible purposes, soaps, and as a linseed substitute. A malagma made from the seed is a folk remedy for condylomata of the joints. Leaves astringent has been used in diarrhoea. The juice of unripe fruit astringent has been used to treat throat affections. Dried fruit as demulcent, cooling, sweet, laxative, stomachic, has been used in thirst, body heat, coughs, hoarseness, consumption, and wasting diseases. The fruit, prepared in various manners, is said to be a remedy for mola, uterine tumors, and hardness of the liver, tumors, and cancer.151 Mokni et al.49 evaluated the protective effect of the ethanol extract from V. vinifera seeds and skin against doxorubicin-induced renal toxicity in rats. Animals were treated with the ethanol extract from V. vinifera seeds and skin for 8 days and administered doxorubicin (20 mg/kg) 4 days later. Results showed that doxorubicin induced renal toxicity by affecting the renal architecture and plasma creatinine. Doxorubicin also induced oxidative stress characterized by an increase in MDA, calcium, and H2O2 and a decrease in CAT and SOD. Unexpectedly, doxorubicin increased peroxidase and decreased carbonyl protein and plasma urea. Treatment with V. vinifera extract counteracted almost all adverse effects induced by doxorubicin. Turki et al.50 conducted an investigation of supplementation with grape seed extract capsules (2 g GSE/day) or placebo on chronic kidney disease patients for 6 months. Grape seed ameliorated inflammation by decreasing C-reactive protein and triglyceridemia and counteracted anemia and thrombocytopenia. Grape seed extract is a polyphenolic mixture exhibiting anti-oxidant and anti-inflammatory properties as reported by Turki et al.50 According to Mokni et al.,49 the main compound of grape seed and skin extracts are 2,5-dihydroxybenzoïc acid, gallic acid, and vanillin. Among these phenolic compounds, gallic acid118 and vanillin152 have been well studied for their potent nephroprotection.

Future directions

Research on Tunisian nephroprotective plants has been mainly done in a laboratory setting with a limited number of animals. Thus, additional studies must be done with a greater number of experiments, different animal models, and human subjects. It should be mentioned that this is the first review that summarizes several reports on Tunisian nephroprotective plants. The literature demonstrates that these plants contain bioactive compounds that could be used to treat kidney disease. This review may be valuable to health professionals, scientists, and scholars working in the field of pharmacology and therapeutics to produce new safety drug formulations to treat kidney diseases.

Conclusions

In this review, 29 Tunisian medicinal plants were summarized for their significant nephroprotective activities against renal toxicities in animal models. Lamiaceae family was the most commonly used nephroprotective Tunisian plant. Leaves were maximally used for nephroprotection compared to the other plant parts. In the case of Indian nephroprotective plants, Asif153 also reported that the leaves were most frequently used in the treatment of nephrotoxicity, with the most dominant family being Euphorbiaceae. In this review, most studies focused on drug-induced renal failure, which is a major challenge in medical practice. Other studies focused on other important nephrotoxicity factors, including industrial chemicals, particularly CCl4-induce nephrotoxicity. In general, CCl4 enhanced levels of renal markers (urea and creatinine) in the serum of experimental animals. It also increased oxidative stress markers resulting in increased LPO with a concomitant decrease in SOD, CAT, and GPx in the kidney. To protect against this nephrotoxicity, some medicinal plants, have curative properties attributed to various complex chemical substances as organosulfur compounds, polyphenols, polysaccharides, phenylpropanoids, terpenes, and alkaloids.

Abbreviations

ALP: 

alkaline phosphatase

CAT: 

catalase

CCl4: 

carbon tetrachloride

GPx: 

glutathione peroxidase

GSH: 

reduced glutathione

H2O2: 

hydrogen peroxide

LPO: 

lipid peroxidase

MDA: 

malondialdehyde

PCO: 

protein carbonyl

ROS: 

reactive oxygen species

SOD: 

superoxide dismutase

Declarations

Acknowledgement

None.

Funding

None.

Conflict of interest

The authors declare no conflicts of interest.

Authors’ contributions

Conceptualization (WAW); writing (WAW); methodology (WAW); investigation (WAW); formal analysis (WAW); data curation (WAW); resources (WAW); supervision (MST); writing, review, and editing (WAW). All authors have read and agreed to the published version of the manuscript.

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Tunisian Nephroprotective Plants: A Review

Wissem Aidi Wannes, Moufida Saidani Tounsi
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