The Renal Effects of Blood Glucose-Lowering Plant-Derived Extracts in Diabetes Mellitus—an Overview

Abstract

Diabetes mellitus, a disorder characterized by chronic hyperglycemia and excessive urine excretion, is associated with complications such as atherosclerosis, cardiac dysfunction, and nephropathy. Renal disease, which develops through a number of metabolic pathways in diabetes, is characterized by functional as well as structural abnormalities of the kidney. The most common cause of end-stage renal disease (ESRD) is diabetic nephropathy, which accounts for significant morbidity and mortality. Current conventional diabetes therapy using blood glucose-lowering medications has limitations in averting the development of renal diseases. The onset of diabetic nephropathy is associated with a progressive rate of decline in renal function, urinary albumin excretion, and glomerular filtration rate (GFR). Diabetes mellitus treatment should therefore aim to intervene on promoters of the decline in renal function in diabetes to avert adverse outcomes. Preventing the pathogenesis of nephropathy with therapeutic interventions based on specific alterations in kidney function represents a plausible approach. Cumulative evidence suggests that some herbal extracts with hypoglycaemic properties may have beneficial effects on some processes associated with a decline in renal function, as well as reduce the severity of nephropathy in diabetic experimental animals. On the other hand, some herbal extracts may be hazardous in diabetes, as reports indicate impairment of renal function. This review outlines current evidence supporting plant extracts with the potential of averting progressive renal diabetic complications as well as the nephrotoxicity of some herbal extracts.

Keywords:

• renal function
• diabetes mellitus
• diabetic nephropathy
• medicinal plants

INTRODUCTION

Diabetic nephropathy, the predominant cause of end-stage renal disease (ESRD) in Western countries, is a major cause of death and illness in diabetes.^[1,2] The morbidity and mortality associated with diabetic nephropathy have placed in the forefront attempts to discover new therapies that may prevent the advent of diabetic nephropathy. The onset of nephropathy is associated with a progressive decline in renal function. Factors that denote the decline of renal function in diabetes include decreased glomerular filtration rate (GFR) and increased blood pressure and urinary albumin excretion.^[3,4] The prevention of the occurrence and progression of diabetic nephropathy have become important clinical issues.^[2] To date, treatments for progressive diabetic nephropathy are antihypertensive agents, particularly inhibitors of the renin-angiotensin system (RAS), angiotensin-converting enzyme (ACE), angiotensin receptor antagonists, or their combination.^5-9 Although these treatments slow down the progression toward ESRD, clinical trials suggest that there is no effective treatment for diabetic nephropathy.^[2] However, a substantial body of evidence suggests that herbal extracts possess a range of important pharmacological properties that may retard the progressive decline in renal function in diabetes.^[10,11] Studies suggest that plant extracts with hypoglycaemic properties alleviate kidney complications associated with clinical diabetes mellitus ^12-15 and reduce the severity of nephropathy in experimental animals.^[16] Indeed, Chinese herbal extracts indicate therapeutic potential against diabetic nephropathy in terms of their effects on associated diabetic metabolic disorders.^[17] The mechanisms by which the plant extracts influence kidney function at molecular, physiological, and biochemical levels could be useful in the treatment of renal complications in diabetes. Anti-diabetic extracts of Sclerocarya birrea [(A. Rich) Hochst.] [Anachardiaceae], Persea americana (Miller) [Lauraceae], and Ficus thonningii (Blume) [Moraceae] have been reported to reverse the inability of the kidney to excrete Na⁺ in streptozotocin (STZ)-diabetic rats.^[18,19] On the other hand, observations indicate that some anti-diabetic herbal extracts may impair kidney function, as indicated by an increased renal fluid and electrolyte retention and reduced GFR.^[20,21] It is therefore possible to base diabetes treatment on specific alterations in kidney function to avert adverse outcomes. In this review, we discuss recent advances in the research on some plant extracts for pharmacological intervention in renal complications in diabetes and kidney-related injuries as well as the potential for nephrotoxicity from other plant extracts. The following sections discuss current evidence on therapeutic intervention with plant extracts and beneficial effects on the kidney in diabetes.

KIDNEY FUNCTION CHANGES IN DIABETES MELLITUS

Sustained hyperglycaemia has been shown to be the major risk factor responsible for the development of a decline in kidney function in diabetic patients^22–24 and experimental animals.^{[20,21,25,26]} Common clinical manifestations of impaired kidney function in diabetes mellitus include hypertension, protenuria, declining GFR, as well as histological characteristics such as glomeruloscelorosis.

METABOLIC CHANGES AND MANAGEMENT IN DIABETES

Kidney pathophysiology in diabetes is precipitated by interactions between metabolic and haemodynamic factors. The changes may be as a result of the effects of excess glucose directly on kidney cells or indirectly through pathways that involve formation of oxidants and advanced glycation end products.^[22,27,28] Chronic hyperglycaemia accelerates the activation of the formation of advanced glycation end-products (AGEs), polyol pathway, and the protein kinase C pathway.^29-32 The metabolic factors are synergistically correlated with one another, and thus an effective treatment with widespread effects continues to be required. Therapeutic interference with the metabolic pathways involved in the development of diabetic nephropathy, however, preserves the structure of kidneys in experimental animals.^[33]

Advanced Glycation End Products (AGEs)

AGEs are a group of molecules formed from the reaction of reducing sugars with free amino groups of proteins, lipids, and nucleic acids. The interaction of AGE with its receptor (RAGE) activates several intracellular signaling pathways, such as mitogen-activated protein kinase, nuclear factor _KB, and AP-1, and increases the production of cytokines.^[34] The effects are associated with increased production of growth factors^[35] and reactive oxygen species (ROS).^[27,36] The AGE-RAGE binding leads to albuminuria and mesangial expansion resulting in glomerular sclerosis.^{[27,28,36–38} The events described lead to diabetic complications, which include retinopathy, nephropathy, and atherosclerosis. Therefore, the AGE-RAGE pathway is considered as a candidate molecular target for the prevention and treatment of diabetic nephropathy.^[39]

The accumulation of AGEs can be prevented by antioxidants like flavonoids or by preventing the glucose-dependent formation of intermediate products (Amadori, Schiff bases, or Milliard products). Indeed, blocking or deleting AGE's receptor (RAGE) in experimental animals reverses atherosclerosis.^[40] Amino guanidine and pyridoxamine, AGEs formation inhibitors, have renoprotective effects in diabetic animals.^[38,41] Furthermore, the inhibition of AGEs effects can be achieved through breaking the AGEs cross links by drugs such as alagebrium or by inhibiting AGE signal transduction.^[38] Indeed, it has been reported that metformin, a plant-derived anti-diabetic drug, may be useful in the prevention of the development of AGEs.^[42] Extracts of Panax quinquefolium (Linnaeus) [Araliaceae], resveratrol, a phytoestrogen derived from Vitis vinifera (Linnaeus) [Vitaceae]; curcumin from Curcuma longa (Linnaeus) [Zingiberaceae]; and glycosides from Stelechocarpus cauliflorus (R.E. Fr) [Annonaceae] have also been reported to inhibit formation of AGEs or RAGE.^[28,43-45

Polyol Pathway

The activation of the polyol pathway (aldose reductase pathway) is involved in the pathogenesis of renal complications in diabetes mellitus via hyperglycaemia-induced glomerular and tubular cell damage.^[46] Hyperglycemia-induced renal polyol pathway activity occurs in tandem with oxidative changes, stimulation of the formation of AGEs, and protein kinase C (PKC) pathways. In addition, the pathway stimulates PKC-mediated glomerular prostaglandin production and loss of mesangial cell contractility^[47] to possibly cause hyperfiltration and glomerular dysfunction in diabetes mellitus. Inhibition of aldose reductase with synthetic drugs such as zenarestat and sorbinil and plant extracts has been reported to prevent or alleviate in part some of the diabetic renal complications.^[27,47,48] Quercetin, silymarin, flavonoids, and puerarin isolated from plants inhibit aldose reductase activity.^[15] In addition, glycosides engeletin and astilbin isolated from Stelechocarpus cauliflorous [Annonaceae] leaves inhibit aldose reductase activity.^[45] Furthermore, rhizomes of Coptis chinensis (Franch) [Ranunculaceae]- and Phellodendron amurense (Ruprecht) [Rutaceae]-derived berberine inhibits aldose reductase activity with concomitant inhibition of oxidative stress.^[49]

Protein Kinase C

The activation of protein kinase C (PKC) and its isoforms has been implicated in the pathogenesis of diabetic nephropathy.^[50] The intracellular mechanism is the glucose-induced de novo synthesis of diacylglycerol, one of the intracellular activators of PKC isoforms^[27] implicated in the pathogenesis of diabetic nephropathy.^{[27,28,51,52]} In addition to high glucose, several nephrotoxic factors such as inflammatory mediators, growth factors, hypoxia, and vasoactive hormones activate PKC-ß isoform,^{[27,50,51,53–56} which is highly expressed in various forms of glomerulonephritis.^[57] Thus, the inhibition of PKC system may provide a new therapeutic strategy to prevent complications of diabetes. Indeed, ruboxistaurin, a specific inhibitor of PKC-ß, has shown efficacy in the treatment of diabetic renal abnormalities both in diabetic patients and experimental animals.^{[28,50,58,59]} Parthenolide, a plant-derived extract, has also been reported to avert a declining GFR and reduce proteinuria in experimental animals.^[60] Interestingly, PKC-modulating compounds are easily obtained from vegetables, berries, spices, tea, and wine, including quercetin.^61–64

Herbal-Related Nephrotoxicity

As herbal medicine becomes increasingly practiced worldwide, reports of adverse effects occasionally appear in literature, and questions are being asked about safety. Plants can contain pharmacologically useful and active compounds, but unsurprisingly, they can contain toxic substances. Indeed, current evidence also indicates that certain herbal extracts and plant products ameliorate the deterioration of kidney function in diabetes mellitus.^[65] Against this background is the observation that the Hypoxis hemerocallidea extract (i.e., the corm, popularly known as the “African Potato”), besides possessing anti-diabetic properties, impairs kidney function, as indicated by its increasing renal fluid and electrolyte retention and reducing GFR in experimental animals.^[66]

EXTRACTION AND ISOLATION OF BIOACTIVE PLANT COMPOUNDS

The chemical constituents of medicinal plant extracts, which determine the therapeutic activity, can be classified into major groups, such as essential oils, alkaloids, acids, steroids, tannins, and saponins. Each one of these classes of chemicals has a preferred effective method of extraction. Hence, the techniques for the extraction and analysis of medicinal plants play an important role in ensuring and providing high-quality herbal products. The techniques include solid-phase microextraction, supercritical-fluid extraction, pressurized-liquid extraction, solid-phase extraction, and surfactant-mediated extraction.^67–69 The most commonly used sample-preparation techniques for the extraction, clean up, and concentration of analytes from medicinal plants or herbal materials are depicted in Figure 1.

Figure 1.  Isolation and extraction of active ingredients from medicinal plants.

We have used organic solvents to extract bioactive compounds from plants such as Syzygium cordatum and Ficus thonningii.^[70] Investigations have also been extensively conducted with triterpenoids, xanthones, polysaccharides, or flavonoids isolated from plants.^[13] An overview of some effects of the renal effects of some hypoglycaemia-inducing plant species obtained from current literature is given in Table 1.

Table 1  Partial survey of medicinal plants/plant extracts that influence renal function/structure

Medicinal plants/plant extracts	Anti-diabetic properties	Renal effects	References
Baccopa monnieri	−	Anti-oxidant activity	^[71]
Cornus officinalis	+	↓ Kidney ROS	^[72]
Gongronema latifolium	+	↑ Superoxide dismutase (SOD), glutathione peroxidase	^[73]
Rheum emodi	−	(GPx), reduced glutathione (GSH), catalase, etc.	^[74]
Vigna angularis	−	Renoprotection	^[75]
Helicrysium ceres	+	Amelioration of renal function	^[76]
Oleanolic acid (Syzygium cordatum)	+	↑ GFR	^[77]
Sclerocarya birrea	+	↓ Plasma urea and creatinine concentrations	^[19]
Opunthia megacantha	+	↓ Urinary protein concentration	^[20]
Persea americana	+		^[78]
Jawarishi Zarooni Sada (a polyherbal unani formulation)	−		^[79]
Corni fructus	+	Maintenance of kidney structure	^[80]
Curcumin (Curcumin longa)	+	↓ Kidney levels of RAGE, AGE, TGF-ß1	^[81]
Allium sativum and Zingiber officinale	+	↓ Extra-cellular matrix proteins (e.g., fibronectin)	^[82]
Momordica charantia	+	↓ Renal hypertrophy	^[26]
Coptis chinensis and Phellodendron amurense	+		^[49]
Hypoxis hemerocallidea	+	Reno-toxic effects	^[66]
Opunthia megacantha	+	↓GFR↑ serum urea and creatinine concentrations	^[83]

CONCLUSION

Literature evidence suggests that some plant extracts contain pharmacologically active compounds, which may have beneficial roles in slowing progressive renal disease. Furthermore, there are clearly many points in diabetes at which therapeutic approaches with plant-derived extracts could be tried to provide renoprotection. Targeting multiple options of altered kidney function in diabetes may be more appropriate to retard the development of diabetic nephropathy.

ACKNOWLEDGMENTS

The authors report no conflicts of interest.