Renal Failure

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The Renal Effects of Blood Glucose-Lowering

Plant-Derived Extracts in Diabetes Mellitus—an
Overview

R. F. Mapanga & C. T. Musabayane

To cite this article: R. F. Mapanga & C. T. Musabayane (2010) The Renal Effects of Blood
Glucose-Lowering Plant-Derived Extracts in Diabetes Mellitus—an Overview, Renal Failure, 32:1,
132-138, DOI: 10.3109/08860220903367585

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Renal Failure, 32:132–138, 2010
Copyright © Informa UK Ltd.
ISSN: 0886-022X print / 1525-6049 online
DOI: 10.3109/08860220903367585
STATE OF THE ART REVIEW
LRNF
The Renal Effects of Blood Glucose-Lowering Plant-Derived Extracts
in Diabetes Mellitus—an Overview
R.F. Mapanga and C.T. Musabayane
Phytomedicine
Discipline of Human Physiology, Faculty of Health Sciences, University of KwaZulu-Natal, Private Bag X54001, Durban,
South Africa
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 nephr-
opathy 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 cur-
rent 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
Received 24 June 2009; revised 29 July 2009; accepted
24 September 2009.
Address correspondence to Professor C.T. Musabayane,
Department of Human Physiology, School of Medical Sciences,
University of KwaZulu-Natal, Private Bag X54001, Durban 4000,
South Africa; Tel.: (27) (31) 260 7975; Fax: (27) (31) 260 7132;
E-mail: musabayanec@ukzn.ac.za
132
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 mor-
bidity and mortality associated with diabetic nephropathy
have placed in the forefront attempts to discover new ther-
apies 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 sys-
tem (RAS), angiotensin-converting enzyme (ACE), angio-
tensin receptor antagonists, or their combination.[5–9]
Although these treatments slow down the progression
toward ESRD, clinical trials suggest that there is no effec-
tive 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 poten-
tial against diabetic nephropathy in terms of their effects
on associated diabetic metabolic disorders.[17] The mecha-
nisms by which the plant extracts influence kidney func-
tion 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
 Phytomedicine
(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 elec-
trolyte 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 benefi-
cial 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 mani-
festations 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 glu-
cose 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. Therapeu-
tic 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 reac-
tion of reducing sugars with free amino groups of proteins,
133
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 anti-
oxidants 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 pyridox-
amine, AGEs formation inhibitors, have renoprotective
effects in diabetic animals.[38,41] Furthermore, the inhibi-
tion of AGEs effects can be achieved through breaking the
AGEs cross links by drugs such as alagebrium or by inhib-
iting 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 glyco-
sides from Stelechocarpus cauliflorus (R.E. Fr) [Annon-
aceae] 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 complica-
tions 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 prostag-
landin production and loss of mesangial cell contractility[47]
to possibly cause hyperfiltration and glomerular dysfunc-
tion 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] Quer-
cetin, silymarin, flavonoids, and puerarin isolated from
plants inhibit aldose reductase activity.[15] In addition,
134 R.F. Mapanga and C. T. Musabayane

glycosides engeletin and astilbin isolated from
Stelechocarpus cauliflorous [Annonaceae] leaves inhibit
aldose reductase activity.[45] Furthermore, rhizomes of
Coptis chinensis (Franch) [Ranunculaceae]- and Phello-
dendron amurense (Ruprecht) [Rutaceae]-derived ber-
berine 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 dia-
betic 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 addi-
tion 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 glomerulo-
nephritis.[57] Thus, the inhibition of PKC system may pro-
vide 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 experi-
mental 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] Inter-
estingly, 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

Plant material

Air dried and milled Air dried and milled

into fine powder into fine powder

Sequential extracted with

Soaked in an organic solvent for 24–72h hexane, methanol, ethy lacetate
with shaking followed by and dichloromethane followed by
filtration filtration

Filtrate concentrated in a rotary Respective solubles concentrated

evaporator and air dried under in a rotary evaporator
nitrogen

Organic solvent crude extract Further extraction with

chromatographic techniques

Pure compound obtained

and structure confirmed by
NMR spectroscopy or HPLC

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

 Phytomedicine 135

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

Anti-diabetic
Medicinal plants/plant extracts 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]

[76]
Helicrysium ceres + Amelioration of renal function
Oleanolic acid (Syzygium cordatum) + ↑ GFR [77]

Sclerocarya birrea + ↓ Plasma urea and creatinine concentrations [19]

Opunthia megacantha + ↓ Urinary protein concentration [20]

[78]
Persea americana +
Jawarishi Zarooni Sada (a polyherbal − [79]

unani formulation)
[80]
Corni fructus + Maintenance of kidney structure
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]

[49]
Coptis chinensis and Phellodendron +
amurense
[66]
Hypoxis hemerocallidea + Reno-toxic effects
Opunthia megacantha + ↓GFR↑ serum urea and creatinine concentrations [83]

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 extrac-
tion. 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.
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 cur-
rent literature is given in Table 1.
CONCLUSION
Literature evidence suggests that some plant extracts con-
tain pharmacologically active compounds, which may have
beneficial roles in slowing progressive renal disease. Further-
more, there are clearly many points in diabetes at which thera-
peutic 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.
136 R.F. Mapanga and C. T. Musabayane
ACKNOWLEDGMENTS
The authors report no conflicts of interest.
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