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. 2018 Dec 7;234(8):12161–12172. doi: 10.1002/jcp.27950

Protective effects of plant‐derived natural products on renal complications

Habib Yaribeygi 1,✉, Luis E Simental‐Mendía 2, Alexandra E Butler 3, Amirhossein Sahebkar 4,5,6,✉
PMCID: PMC13484185  PMID: 30536823

Abstract

Diabetic nephropathy is the leading cause of renal failure worldwide. This debilitating disorder has several underlying pathophysiologic mechanisms, and therefore a variety of pharmacologic agents have been developed to prevent or treat diabetic nephropathy; however, synthetic drugs may possess unfavorable side effects. In response to this, the global use of herbal‐based pharmacologic agents is increasing among diabetic patients. Numerous studies have reported therapeutic benefits of herbal‐based compounds against diabetes‐induced renal dysfunction. These agents can prevent renal dysfunction and improve renal function by blocking or suppressing deleterious pathways such as oxidative stress, inflammation, apoptosis, necrosis, and nitric oxide deprivation that lead to vascular injuries. In the current study, we have reviewed the beneficial properties of the most common herbal agents used in renal complications and diabetic nephropathy.

Keywords: crocin, curcumin, diabetic nephropathy, garlic, herbal, inflammation, oxidative stress, TGF‐β

Numerous studies have reported therapeutic benefits of herbal‐based compounds against diabetes‐induced renal dysfunction. These agents can prevent renal dysfunction and improve renal function by blocking or suppressing deleterious pathways such as oxidative stress, inflammation, apoptosis, necrosis, and nitric oxide deprivation that lead to vascular injuries. In the current study, we have reviewed the beneficial properties of the most common herbal agents used in renal complications and diabetic nephropathy.

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1. INTRODUCTION

The incidence of diabetes mellitus (DM) is growing rapidly worldwide (Mayer‐Davis et al., 2017). As the incidence of DM increases, so too are diabetic complications (Gregg et al., 2014). Uncontrolled chronic hyperglycemia can induce several pathophysiologic molecular pathways and stimulate pathogenic mechanisms leading to detrimental outcomes in various tissues such as kidneys, brain, retina, and the cardiovascular system (Gregg et al., 2014; Yaribeygi, Butler, Barreto, & Sahebkar, 2018d). Diabetic nephropathy (DN) is one of the most prevalent diabetic complications and is related to diabetes‐induced microvascular injury, renal dysfunction, and overt albuminuria (Yaribeygi, Mohammadi, Rezaee, & Sahebkar, 2018h). This debilitating disorder is also the major cause of end stage renal disease (ESRD) leading to the need for hemodialysis in diabetic patients (Yaribeygi, Farrokhi, Rezaee, & Sahebkar, 2018e). Moreover, DN is likely the leading cause of death in diabetic subjects with uncontrolled hyperglycemia (Ang, Heng, Saxena, Liew, & Chong, 2016). Therefore, many studies in recent years have focused upon design of new preventive or therapeutic strategies for DN (Yaribeygi et al., 2018e, 2018h).

Whilst current antidiabetic therapies commonly used in clinical practice, namely insulin, sulfonylureas, dipeptidyl peptidase 4 (DPP‐4) inhibitors, thiazolidinediones (TZDs), biguanides, sodium‐glucose co‐transporter type 2 inhibitors (SGLT2i), glucagon‐like peptide‐1 (GLP‐1 receptor agonists), and ALPHA GLUCosidase inhibitors (AGi), are effective hypoglycemic effects, they may have unfavorable side effects (Association, 2018; Chaudhury et al., 2017). In addition to these synthetic hypoglycemic drugs, several plants and herbal agents are recognized to normalize hyperglycemia and prevent diabetes‐induced complications with few, if any, detrimental side effects (Newman & Cragg, 2012; Shafi, Tabassum, & Ahmad, 2012). Moreover, evidence in recent years suggests that some types of herbal‐based antidiabetic agents can play a significant role in the treatment or prevention of DN (Sharma, Kulkarni, & Chopra, 2006; Yaribeygi, Mohammadi, Rezaee, & Sahebkar, 2018g). Thus, the use of natural‐based and herbal agents for lowering blood glucose and preventing/treating related complications is growing worldwide (Newman & Cragg, 2012). In the current study, we review the latest evidence regarding the possible beneficial effects of naturally occurring hypoglycemic agents against DN development.

2. MOLECULAR MECHANISMS INVOLVED IN THE ONSET OF DIABETIC NEPHROPATHY

DN is characterized by structural and functional changes in the kidney. In the early stage, there is tubular hypertrophy and interstitial fibrosis accompanied by tubular atrophy and arteriolar hyalinosis leading to glomerular hyperfiltration and elevated albumin excretion (AKh, 2014). Many molecular pathways are candidates for involvement in the onset and progression of DN development including the renin‐angiotensin system (RAS), PKC1 over‐activation, the TGF‐β2 signaling pathway, haemodynamic pathways, metabolic abnormalities, inflammatory responses, TNF‐α3 molecular pathways, advanced glycation end products (AGEs) and oxidative stress. (Fujita et al., 2012; MA & WU, 2014; Tavafi, 2013; Yamagishi & Matsui, 2010; Yaribeygi, Atkin, Katsiki, & Sahebkar, 2018a; Yaribeygi, Butler, Atkin, Katsiki, & Sahebkar, 2018c; Yaribeygi et al., 2017; Yaribeygi, Katsiki, Butler, & Sahebkar, 2018f). Activation of RAS increases angiotensin II concentrations resulting in vasoconstriction of the efferent arterioles with release of pro‐inflammatory cytokines and profibrotic molecules (AKh, 2014). Also, elevated levels of both endothelin‐1 and urotensin II induce vasoconstriction. Increased concentrations of angiotensin converting enzyme have been associated with microalbuminuria and progression of DN (W. Huang, 2001; Rudberg, Bangstad & Osterby, 2000). Additionally, deficiency of endothelial nitric oxide synthase‐derived nitric oxide causes glomerular damage and albuminuria (Kanetsuna et al., 2007). Oxidative stress and reactive oxygen species affect DNA and proteins and may activate cellular stress pathways including PKC, mitogen‐activated protein kinase (MAPK), and NF‐κB, which contribute to the development of DN (Ha, 2000; Haneda, Togawa, Sugimoto, Isono & Kikkawa, 1997). Activation of the polyol pathway results in oxidative stress by increasing the NADH/NAD + ratio (Srivastava SK & Bhatnagar, 2005; Yaribeygi, Atkin, & Sahebkar, 2018b). Elevated TNF‐α increases albumin permeability through the production of ROS (McCarthy ET et al., 1998; Radeke HH, Topley, Flöge, Habermehl & Resch, 1990). Formation of AGEs may cause renal damage by alteration in the function of proteins, oxidative stress, pro‐inflammatory cytokines, and growth factors (Sheetz, 2002). Increased glomerular expression of TGF‐β1 and CTGF induce extracellular matrix formation and fibrosis (AKh, 2014). PKC activation promotes activity of angiotensin II, nitric oxide disturbance, endothelial dysfunction, and activation of MAPK and NF‐κB (Derubertis, 1994; Noh, 2007). MAPKs activate NF‐κB, regulating gene expression of cytokines, chemokines, and adhesion molecules. Activation of NF‐κB modulates the inflammatory response in progressive DN (Hofmann MA et al., 1998; Schmid et al., 2006). These pathways overlap and interact with each another, thereby affecting their biological activities. Consequently, any pharmacologic factor able to inhibit or suppress these detrimental pathways may be considered a renoprotective agent and a potential therapeutic agent in the management of DN.

3. RENOPROTECTIVE NATURAL‐BASED AGENTS

Several naturally occurring compounds have been identified as having renoprotective roles in the diabetic milieu (Khaki & Fathiazad, 2012; Sharma et al., 2006; Yaribeygi et al., 2018g).

3.1. Crocin

Crocin is one of the active constituents of saffron (Crocus sativus L.) extract, which is a water soluble beta‐carotene with known potent biochemical activity (Yaribeygi et al., 2018g).

Consistent with the medicinal properties reported for saffron (Shafiee, Arekhi, Omranzadeh, & Sahebkar, 2017; Yaribeygi, Sahraei, Mohammadi, & Meftahi, 2014), recent evidence suggests Crocin as a candidate therapeutic agent for a range of diabetes‐induced complications (Nikbakht‐Jam et al., 2015; Rahiman, Akaberi, Sahebkar, Emami, & Tayarani‐Najaran, 2018; Yaribeygi et al., 2018g). Crocin is a potent antioxidant, having anti‐inflammatory and antiapoptotic effects (Yaribeygi et al., 2017; Yaribeygi et al., 2018g). Despite an increasing body of evidence suggesting a beneficial role for Crocin in various tissues in the diabetic milieu, to date only three studies have evaluated the possible renoprotective effects of Crocin in diabetic kidneys (Altinoz, Oner, Elbe, Cigremis, & Turkoz, 2015; Yaribeygi et al., 2017; Yaribeygi et al., 2018g).

We recently reported that Crocin significantly ameliorates the deleterious molecular pathways involved in DN and improves renal function in an experimental model of diabetes (Yaribeygi et al., 2018g). We observed that treatment of diabetic animals with Crocin significantly reduced interleukin‐18 (as a marker of inflammation in the kidney), Nox‐4 (nicotinamide adenine dinucleotide phosphate oxidase‐4, as a major source of free radicals in kidneys) and p53 (as a primary inducer of apoptosis) and so prevented renal injury and reduced albuminuria in diabetic rats (Yaribeygi et al., 2018g). Crocin lowered creatinine in plasma and increased its urinary excretion, thereby enhancing the excretion of uric acid and urea in urine, indicative of improvement in renal function (Yaribeygi et al., 2018g).

Altinoz and colleagues in 2015 also demonstrated that Crocin therapy in diabetic rats reduced renal injury and prevented DN, likely by amelioration of oxidative stress (Altinoz et al., 2015). Crocin can potentiate the antioxidant defense system (ADS) in renal tissues by causing an increase in superoxide dismutase, catalase and glutathione content of diabetic kidneys and decreasing oxidative damage by lowering the concentration of malondialdehyde (MDA; Yaribeygi et al., 2017; Yaribeygi et al., 2018g). Moreover, Crocin reduced histological damage by amelioration of inflammatory and oxidative stress pathways (Yaribeygi et al., 2017; Yaribeygi et al., 2018g).

To date, there are no clinical studies using Crocin in DN, though these are clearly indicated.

3.2. Garlic extract

Garlic is a plant from the Allium family which is widely consumed as a food flavoring, but also traditionally used as a pharmacological agent, especially in its aged form (Ali, Al‐Qattan, Al‐Enezi, Khanafer, & Mustafa, 2000). Garlic extract contains several ingredients that are therapeutically useful, for example, for correction of the glycemic and lipidemic profile of plasma as well as to moderate blood pressure (Ali et al., 2000; Cicero et al., 2017; Sahebkar et al., 2016b; Thomson, Al‐Qattan, Bordia, & Ali, 2006). Some studies have suggested a beneficial role for garlic extract in improving renal function and preventing diabetic complications (Ahmad & Ahmed, 2006; Iqbal & Athar, 1998; Maldonado et al., 2003).

Iqbal and Athar (1998) reported that garlic extract inhibits iron‐dependent nephrotoxicity and so improves renal function in an animal model of nephrotoxicity. Maldonado et al. (2003) observed that garlic extract prevents gentamycin‐induced toxicity in renal tissue by potentiating ADS elements and suppressing oxidative damage. Moreover, Kabasakal et al. (2005) demonstrated that garlic extract suppressed oxidative damage in renal tissue during ischemia‐reperfusion periods. We also have evidence in support of a beneficial role of garlic extract in prevention/treatment of DN (Al‐Qattan, Thomson, & Ali, 2008; Mariee, Abd‐Allah, & El‐Yamany, 2009).

Mariee et al. (2009) reported that garlic extract acts as a key scavenger for free radicals in renal tissue and prevents diabetes‐induced nephropathy by amelioration of oxidative stress and improvement of microvascular function via enhancement of nitric oxide bioavailability in the renal vasculature network. Al‐Qattan et al. (2008) demonstrated that 7 weeks treatment with garlic extract in diabetic rats significantly decreased serum glucose and prevented histological kidney damage (Al‐Qattan et al., 2008). Shiju, Rajesh, and Viswanathan (2013) found that aged garlic extract markedly protected renal tissue against diabetes‐induced injuries via its hypoglycemic, hypolipidemic, and antioxidant actions.

Thomson, Al‐Qattan, Mansour, and Ali, (2013) reported the effects of garlic extract on markers of DN, finding that garlic extract reduced serum levels of insulin and decreased urinary creatinine, protein and albumin excretion, and reduced oxidative damage, thereby improving renal function in diabetes‐induced animals. Collectively, this evidence suggests that garlic extract can protect kidneys against hyperglycemia‐induced damage by reducing oxidative damage and improving insulin sensitivity, though other molecular mechanisms, including anti‐inflammatory effects, may also be involved (Atkin, Laight, & Cummings, 2016).

3.3. Olive oil

The olive is a species of small tree in the Oleaceae family, traditionally and primarily valued for their nutrient fruit (Beauchamp et al., 2005). Olive oil is consumed as a food additive and has prime pharmacologic effects as an antioxidant (Fitó, de la Torre, & Covas, 2007).

Some evidence suggests that olive oil has potent renoprotective effects in a number of conditions including diabetes (Hoile et al., 2014; Tripoli et al., 2005). Olive oil is rich in poly unsaturated fatty acids (omega‐3) and additionally contains several forms of polyphenolic compounds which harbor potent antioxidative properties, and can therefore protect against oxidative stress‐induced disorders (Fitó et al., 2007).

The traditional Mediterranean diet, where there is a high consumption of olive oil, is associated with a 50% lower risk for chronic kidney disease and only minimal risk of acute kidney dysfunction (Chauveau et al., 2017). Thus, many studies have suggested the Mediterranean diet for diabetic patients to improve renal function and prevent DN (Chauveau et al., 2017). A multiethnic cohort study by Khatri et al. (2014) demonstrated that the Mediterranean diet is associated with a lower risk of adverse effects on eGFR (estimated glomerular filtration rate). A randomized controlled trial by Mitjavila et al. (2013) demonstrated that the Mediterranean diet significantly improved glycemic control and reduced both systemic and DNA‐related oxidative damage. However, in a post hoc analysis of a cohort of patients with Type 2 diabetes (T2DM), the Mediterranean diet had no protective effects against DN, although it did improve retinal status and prevent diabetic retinopathy (Díaz‐López et al., 2018). To date, no direct evidence exists regarding the mechanism by which olive oil prevents/treats DN, but reviewed data strongly suggests that olive oil is a therapeutic agent for improving renal function and delaying onset of DN (Chauveau et al., 2017; Khatri et al., 2014).

3.4. Curcumin

Curcumin is an herbal active ingredient produced mainly by turmeric and used widely as a flavoring and coloring additive agent (Yang et al., 2005). In addition to its use as a dietary supplement and food additive, recent evidence indicates that Curcumin is a potent and biochemically active ingredient (Singh & Aggarwal, 1995; Yang et al., 2005). This bioactive molecule possesses potent antioxidative (Panahi, Alishiri, Parvin, & Sahebkar, 2016a; Panahi, Ghanei, Hajhashemi, & Sahebkar, 2016b; Sahebkar, Serban, Ursoniu, & Banach, 2015b), and anti‐inflammatory (Panahi et al., 2015; Panahi, Sahebkar, Parvin, & Saadat, 2012; Sahebkar, Cicero, Simental‐Mendía, Aggarwal, & Gupta, 2016a), immunomodulatory (Abdollahi, Momtazi, Johnston, & Sahebkar, 2018; Momtazi‐Borojeni et al., 2017), anti‐thrombotic (Keihanian, Saeidinia, Bagheri, Johnston, & Sahebkar, 2018; Tabeshpour, Hashemzaei, & Sahebkar, 2018), cardioprotective (Saeidinia et al., 2018), anti‐ischemic (Bavarsad, Barreto, Hadjzadeh, & Sahebkar, 2018; Mokhtari‐Zaer, Marefati, Atkin, Butler, & Sahebkar, 2018), lipid‐regulating (Ganjali et al., 2017; Panahi et al., 2016b; Panahi et al., 2017a), antitumor (Mirzaei et al., 2016; Momtazi & Sahebkar, 2016; Momtazi et al., 2016), analgesic (Serban et al., 2016), pulmonoprotective (Lelli, Sahebkar, Johnston, & Pedone, 2017), antiarthritic (Panahi et al., 2014) antidiabetic (Panahi et al., 2018) and hepatoprotective (Panahi et al., 2017b; Zabihi, Pirro, Johnston, & Sahebkar, 2017) effects in various diseases. Curcumin can also affect apoptotic and fibrotic pathways and thereby prevent diabetes‐induced tissue injury (Pan et al., 2014; Soetikno et al., 2011).

Some reports indicate a beneficial role of Curcumin on renal function and prevention of nephrotoxicity and DN (Tirkey, Kaur, Vij, & Chopra, 2005). Tirkey et al. (2005) reported that administration of Curcumin for three weeks in rats ameliorated oxidative stress and cyclosporine‐induced renal dysfunction in kidney tissue (Tirkey et al., 2005). Yousef and coworkers in 2010 demonstrated that Curcumin normalized kidney function by suppressing paracetamol‐induced oxidative damage and renal dysfunction in an animal model (Yousef, Omar, El‐Guendi, & Abdelmegid, 2010).

Curcumin can also inhibit diabetes‐induced renal malfunction (Chiu, Khan, Farhangkhoee, & Chakrabarti, 2009). Chiu et al. (2009) showed that one month treatment with Curcumin prevented mesangial expansion and oxidative stress‐induced DN by inhibition of p300 (a transcription factor regulator) and NF‐κb (nuclear factor‐κb).

Soetikno et al. (2011) suggested that other pathways were involved and concluded that Curcumin prevented oxidative damage‐dependent renal dysfunction by modulation of Nrf2 (nuclear factor‐erythroid‐2‐related Factor 2) protein expression with subsequent reduction of NADPH oxidase (nicotinamide adenine dinucleotide phosphatase oxidase) subunit (p67phox and p22phox), cyclooxygenase‐2, TNF‐α (tumor necrosis factor‐alpha), NF‐kb, TGF‐β (transforming growth factor‐beta), and fibronectin accumulation. Sharma, Kulkarni and Chopra (2006) confirmed the antioxidative properties of Curcumin and showed that, after 6 weeks, it prevented DN by suppression of oxidative stress in diabetic animals.

Curcumin may prevent DN by suppression of inflammation in kidneys (Soetikno et al., 2011a). Soetikno et al. (2011a) demonstrated that eight weeks of Curcumin administration in diabetic animals prevented DN by inhibition of macrophage infiltration and downregulation of TNF‐α, IL‐1β (interleukin‐1 beta), ICAM‐1 (intercellular adhesion molecule‐1), MCP‐1 (monocyte chemotactic protein‐1) and TGF‐β1. Pan et al. (2012) provided further evidence and suggested that Curcumin reduces diabetes‐induced nephropathy via inhibition of inflammatory responses via JNK4/NF‐κb pathway inactivation (Pan et al., 2012). As suggested by Huang et al. (2013), Curcumin may act by inactivation of the SphK1‐S1P (sphingosine kinase 1‐sphingosine 1‐phosphate) signaling pathway that is commonly activated during DN. It has also been suggested that Curcumin may prevent DN by inhibition of PKC‐α and PKC‐β1, leading to lower expression of TGF‐β1, CTGF (connective tissue growth factor), osteopontin, and p300 and ECM (extracellular matrix) proteins such as fibronectin and type‐IV collagen (Soetikno et al., 2011b).

3.5. Cinnamon

Cinnamon is an aromatic flavoring and food additive spice produced by cinnamomum trees. This spice also has medicinal applications relating to its active ingredients such as cinnamaldehyde and eugenol (Mang et al., 2006).

Cinnamon has potent pharmacological properties (Mang et al., 2006). It can improve lipidemic and glycemic profiles as well as sensitizing peripheral tissues to insulin (Maierean et al., 2017; Mang et al., 2006; Wang et al., 2007). Cinnamon has protective effects against oxidative stress and inflammation (Moselhy & Ali, 2009; Tung, Chua, Wang, & Chang, 2008). It can modulate apoptotic and fibrotic processes in various tissues by altering mediator molecules (Hagenlocher et al., 2017; Koppikar et al., 2010). Cinnamaldehyde offers protection against endothelial dysfunction in diabetes, which is commonly observed in DN, via Nrf2 activation and induction of downstream pathways (Wang et al., 2015).

Cinnamon also has beneficial influences on renal function (Nasri, Madihi, & Marikhi, 2013a). Cinnamaldehyde significantly improves oxidative stress in renal tissues by suppression of free radical generation and potentiation of ADS elements (Gowder & Devaraj, 2006). Chao, Chang, Shih, and Huang (2010) demonstrated that cinnamaldehyde prevents diabetes‐induced mesangial expansion and development of DN by downregulation of collagen type‐IV, fibronectin, and α‐SMA (α‐smooth muscle actin) . Yan et al. (2015) reported that beneficial ingredients of cinnamon include prevention of DN by inhibition of fibronectin, MCP‐1, and IL‐6 in mesangial cells of diabetic animals. Mishra, Bhatti, Singh, and Ishar (2010) reported that cinnamon oil containing about 98% cinnamaldehyde significantly improved the histological injuries found in the early stages of DN in tubules, the mesangial space and the glomerulus of diabetic animals . Zheng et al. (2011) suggested that cinnamaldehyde prevents DN by inhibition of oxidative damage and downregulation of TGF‐β1, collagen type‐4 and p21 (p21/WAF1Cip1).

Overall, cinnamon has beneficial potential as an antioxidant, an anti‐inflammatory agent and by improving insulin sensitivity as well as protecting against fibrosis, making it a candidate herbal‐based therapy for use in diabetic patients to prevent DN (Guo et al., 2017; Zheng et al., 2011).

3.6. Green tea

Green tea is a widely enjoyed drink that is more natural in comparison with black or white tea because it has not undergone the oxidation or whitening chemical processes (Cabrera, Artacho, & Giménez, 2006). The leaves of this plant have a high concentration of polyphenolic compounds known as “catechins” and so its extract exerts potent antioxidant activity in various tissues (Shah et al., 2015). Reports indicate that green tea can prevent oxidative stress‐induced disorders as well as diabetic complications (Mustata et al., 2005; Sabu, Smitha, & Kuttan, 2002). Green tea polyphenols are able to potentiate ADS elements in hepatic cells and kidneys and prevent oxidative damage in these tissues (Sabu et al., 2002). Green tea may also suppress inflammatory responses and their subsequent outcomes (Donà et al., 2003), although opposite findings have been reported (Fukino, Shimbo, Aoki, OKUBO, & ISO, 2005; Ryu et al., 2006).

Available evidence supports a beneficial role of green tea on renal function (Abdel‐Raheem, El‐Sherbiny, & Taye, 2010; Yokozawa, Young Chung, Qun He, & Oura, 1996). Yokozawa et al. (1996) reported that green tea extract ameliorates mesangial expansion and glomerular sclerotic lesions in diabetic animals . Abdel‐Raheem et al. (2010) demonstrated that green tea polyphenols, as potent antioxidants, ameliorated gentamycin‐induced nephrotoxicity and improved renal function. Yokozawa, Dong, Chung, Oura, and Nakagawa (1997) observed that green tea prevented hypoxia‐induced oxidative stress in a renal epithelial cell line . Ribaldo et al. (2008) reported that green tea therapy attenuated oxidative damage via downregulation of NADPH oxidase in diabetic rats. Yokozawa, Nakagawa, Oya, Okubo, and Juneja (2005) demonstrated that green tea polyphenols protect kidneys against DN in diabetic animals.

Renno, Abdeen, Alkhalaf, and Asfar (2008) showed that green tea prevented glycogen accumulation in the renal tubules, probably because of its hypoglycemic effects, promoting it as a beneficial therapy for DN prevention. Mohabbulla Mohib et al. (2016) confirmed the beneficial role of green tea in DN as it improves oxidative stress via activation of AMPK (AMP‐activated protein kinase) and mTOR (a serine/threonine‐specific protein kinase). A double‐blind randomized clinical trial by Borges, Papadimitriou, Duarte, De Faria, and De Faria (2016) showed that green tea markedly reduced albuminuria and corrected the urinary albumin‐creatinine ratio probably via reduction in podocyte apoptosis in diabetic patients. Kang et al. (2012) demonstrated that green tea prevented DN in both in vitro and in vivo models.

3.7. Ginger

Ginger (Zingiber officinale) is a traditional plant, its roots used as medicine or as a spice and food additive (Kemper, 1999). Ginger has anti‐inflammatory properties as well as antioxidant activity (Ghasemzadeh, Jaafar, & Rahmat, 2010; Thomson et al., 2002). Recent studies have suggested its use as a therapeutic agent in diabetic subjects to improve renal function and prevent DN (Rafieian‐Kopaei & Nasri, 2014). Al‐Qattan et al. (2008) demonstrated that ginger extract attenuated DN progression by correcting histological injuries in glomerular and microvascular renal tissues.

Nasri et al. (2013b) reported that ginger has preventive (not curative) effects against tubular toxicity induced by gentamycin. Tzeng, Liou, Chang, and Liu (2013) showed that an ethanolic extract of ginger prevented diabetes‐induced nephropathy by an AMPK‐dependent mechanism. Afshari et al. (2007) reported that eight weeks of ginger ameliorated oxidative stress and reduced MDA content and was accompanied by ADS potentiation in renal tissues of diabetic rats. Ginger, therefore, may be another possible preventive herbal‐based agent against DN, acting as an antioxidant as well as via AMPK‐dependent pathways (Tzeng et al., 2013).

3.8. Berberine

Berberine is an isoquinoline alkaloid extracted from Rhizoma coptidis and Cortex phellodendri. This medicinal agent exhibits several pharmacological effects such as hypoglycemic, hypolipidemic, antioxidant, and anti‐inflammatory (Ayati et al., 2017; Sahebkar & Watts, 2017; Yin & Ye, 2008). It has been reported that berberine inhibits lipopolysaccharide‐induced cell proliferation and expression of ICAM‐1, TGF‐β1, inducible nitric oxide synthase, and fibronectin through inactivation of the NF‐κB signaling pathway (Jiang et al., 2011). Thus, berberine may reduce the production of extracellular matrix, inflammatory mediators, and profibrotic molecules leading to decreased extracellular matrix accumulation and mitigation of inflammatory response, which attenuates both glomerulosclerosis and renal fibrosis (Jiang et al., 2011). Furthermore, previous studies have observed that berberine activates AMPK signaling pathway through the induction of phosphorylation of acetyl‐CoA carboxylase. Activation of AMPK inhibits the expression of fatty acid synthase, SREBP1c, and peroxisome proliferator‐activated receptor γ, decreasing the production and secretion of lipids, which gradually reduces extracellular matrix accumulation and attenuates glomerulosclerosis and renal tubule fibrosis (Kong et al., 2004). Also, activated AMPK induces free fatty acid oxidation by reducing the production of lipids and consequently the negative effects of dyslipidemia in DN (Kahn BB, Carling & Hardie, 2005). The administration of berberine may delay the progression of DN through inhibition of renal AGEs synthesis (Wu et al., 2012). Additionally, berberine suppresses IκB protein degradation and increases IκB production in glomerular mesangial cells (Ni, Tang, & Wei, 2015b). Berberine inhibits activation of NF‐κB by suppressing the expression of p65 (Ni WJ & Tang, 2015a). Thus, this natural compound improves glomerular basement membrane thickening, glomerulosclerosis and tubulointerstitial fibrosis, emerging as a potential preventive therapy for DN.

3.9. Resveratrol

Resveratrol is a polyphenolic compound with potent antioxidant and free radical scavenger activity. This natural agent also has anti‐inflammatory, anticancer, antidiabetic and neuroprotective effects (Chan et al., 2008; Chi et al., 2007; Hung, & Chen, 2004; Kumar & Sharma, 2013; Singh CK & Ahmad, 2015; Su, Hung, & Chen, 2006; Xu et al., 2014), though its putative cardioprotective actions have recently been disputed (Sahebkar, 2013; Sahebkar et al., 2015a). Previous experimental studies have revealed that resveratrol mitigates renal dysfunction and oxidative stress in DN (Dhaunsi, 2004; Sharma et al., 2006). In this context, resveratrol reduces production of ROS and nitric oxide in high glucose‐induced renal cell damage (Fujii, Kim, Tohda & Nonaka, 2006). Additionally, resveratrol exhibits antiproliferative and antihypertrophic effects by activating AMPK and inhibiting 4E binding protein‐1 and phospho‐ribosomal protein S6 phosphorylation, resulting in attenuation of the development and progression of DN (Ding et al., 2010). Resveratrol may prevent diabetes‐induced renal inflammation and mesangial cell proliferation through suppression of Akt and NF‐κB activation (Xu et al., 2014). Also, this polyphenol decreases lipotoxicity‐related apoptosis and oxidative stress in mesangial cells by phosphorylation of AMPK and activation of silent information regulator T1 and peroxisome proliferator‐activated receptor γ co‐activator 1α signaling (Kim MY et al., 2013). Furthermore, resveratrol has shown a renoprotective action via inhibition of p38 MAPK/TGF‐β1 signaling (Qiao, Wang, Wang & Cui, 2017). Resveratrol inhibits IKK activity, phosphorylation and degradation of IκBα, and consequently nuclear translocation and DNA binding of NF‐κB subunits (Kundu, 2004); therefore, this natural agent may be an effective therapy for prevention of DN.

3.10. Quercetin

Quercetin is a potent antioxidant flavonoid with anticancer and anti‐inflammatory properties (Stewart et al., 2008). Several mechanisms have been described for the beneficial effects of quercetin in DN. Quercetin improves renal dysfunction by inhibiting the mTORC1/p70S6K signaling‐mediated renal tubular epithelial‐mesenchymal transition and renal fibrosis (Lu et al., 2015). Treatment with quercetin mitigates DN and oxidative stress, suggesting a nephroprotective effect (Anjaneyulu M, 2004). This flavonoid attenuates endothelial dysfunction through inhibition of lipopolysaccharide‐induced oxidant production and protein expression of E‐selectin and ICAM‐1 by inducing activation of the nuclear factor erythroid 2‐related Factor 2 and antioxidant enzyme expression (heme oxygenase‐1, NAD[P]H dehydrogenase, quinone 1, and glutamate‐cysteine ligase; Li & Frei, 2016) One study found that quercetin mitigates inflammatory cell infiltration (CD11b+) and improves glucose and lipid metabolism, and renal oxidative stress in DN (Tong, Yan, Li, Ruan & Yang, 2017) Additionally, it has been observed that quercetin treatment ameliorates renal function by reducing proteinuria, fibroblast growth Factor 23, parathyroid hormone, and inorganic phosphate, which are involved in the development and progression of chronic kidney disease (Yang, Liang & Li, 2018). Also, administration of quercetin suppresses the expression of TGF‐β1 and CTGF, enhancing renal function in DN (Lai, Zhang, & Yang, 2012). Thus, quercetin may be considered as an alternative therapeutic option for the treatment of DN.

4. LACK OF CLINICAL TRIALS: THE MAIN CURRENT LIMITATION

Our presented data strongly suggests that herbal‐based nutraceuticals can be considered as potent preventive as well as therapeutic agents for renal complications because they can potentially inhibit and suppress many underlying molecular mechanisms involved in kidney diseases. However, there are some limitations. Clinical trials have evaluated the renoprotective effects of some natural‐based nutraceuticals and confirmed that Curcumin, olive oil and green tea may improve renal function in human studies (Table 1). Clinical trials have also shown beneficial effects of these nutraceuticals in other tissues such as liver and lungs. Further clinical trials to assess the renoprotective effects of Crocin, Quercetin, resveratrol, Berberine, ginger, cinnamon, and garlic extract are still required. Therefore, whilst experimental studies strongly suggest their potential benefits, the lack of adequate clinical trials is the current limitations for development of new realistic preventive/therapeutic strategies for renal complications based on the use of nutraceuticals.

Table 1.

Clinical trials suggesting renoprotective effects for Curcumin, olive oil and green tea

Nutraceuticals Renoprotective effects Ref.
Curcumin Lowers serum urea and induce its urinary excretion Panahi et al. (2016c)
Olive oil Attenuation of oxidative damages and inflammation Díaz‐López et al. (2018)
Green tea Reduction in podocyte apoptosis Borges et al. (2016)
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5. CONCLUSION

Diabetic nephropathy is the leading cause of renal failure and a major reason why diabetic patients require hemodialysis. Many therapeutic strategies have been designed to prevent and treat DN. Apart from synthetic drugs, which may have side‐effects, several herbal‐based agents have been suggested for prevention and therapy (Figure 1). Herbal agents can exert potent beneficial effects and prevent histological injury, such as mesangial expansion, glomerulosclerosis and tubular necrosis; albuminuria is thereby reduced via antioxidant, anti‐inflammatory, antiapoptotic, PKC‐dependent, and AMPK‐dependent molecular pathways. In addition, these herbal‐based agents have few, if any, side‐effects and therefore have a better safety profile when compared to synthetic drugs. However, evidence from randomized controlled trials is lacking and the impact of chronic supplementation with nutraceuticals in preventing DN in diabetic patients merits further investigation.

Figure 1.

Figure 1

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Effects of plant‐derived natural products in the prevention and/or treatment of diabetic nephropathy [Color figure can be viewed at wileyonlinelibrary.com]

CONFLICTS OF INTEREST

The authors declare that there are no conflicts of interest.

Footnotes

1

Protein kinase C.

2

transforming growth factor‐β.

3

tumor necrosis factor‐alpha.

4

Janus kinase.

Contributor Information

Habib Yaribeygi, Email: yaribeygih@chmail.ir.

Amirhossein Sahebkar, Email: sahebkara@mums.ac.ir, Email: amir_saheb2000@yahoo.com.

References

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