VOLUME 9 NUMBER 3 • SEPTEMBER 2012
115
SA JOURNAL OF DIABETES & VASCULAR DISEASE
REVIEW
antihypertensive properties.
16-19
The impact on the kidney varies, with
some species being reno-protective, whereas others had a deleterious
effect on kidney function. By identifying the bio-active compound,
oleanolic acid (OA), which confers reno-protection, we have been able
to demonstrate the effectiveness of this agent in STZ diabetic rats.
The focus of this article is to evaluate current evidence on plant
extracts used for themanagement of hypertension and kidney disease
in diabetes. The beneficial as well as deleterious effects of medicinal
plants in both conditions are discussed based on reports on plants
frequently used in the southern Africa setting. Herein, a medicinal
plant is defined as any plant which provides health-promoting
characteristics, temporary relief or has curative properties.
Antihypertensive therapy and diabetic renal disease
Diabetic complications, which include damage to large and small
blood vessels, can lead to coronary heart disease, stroke and
hypertension, the latter being a well-established major risk factor for
cardiovascular disease that contributes to end-stage renal disease
(
ESRD). Reduction of blood pressure (BP) is therefore an efficient way
of preventing or slowing the progression of ESRD. Conventionally,
reno-protection is achieved through reduction in BP with
antihypertensive regimens.
20-23
Several studies, however, document
that antihypertensive treatment in diabetes not only improves the
quality of life,
24-27
but also reduces renal complications.
28
The major antihypertensive drug classes widely used include
thiazide diuretics, angiotensin converting enzyme (ACE) inhibitors,
angiotensin receptor blockers (ARBs),
β
-
blockers, central sympatho-
lytic agents, calcium channel antagonists and other vasodilators.
However, some antihypertensive agents, for example, thiazide
diuretics and
β
-
blockers deleteriously influence glycaemic control.
29
To date, the most effective treatments for diabetic nephropathy
(
DN) are the antihypertensive drugs, particularly those that target the
renin–angiotensin system (RAS) such as ACS inhibitors, angiotensin-1
receptor antagonists, or their combination.
25,30,31
Although these treat-
ments may retard the progressive decline in renal function in diabetes,
clinical trials suggest that there is no effective treatment for DN.
8
For these reasons, novel anti-diabetic therapeutic agents that
supplement, substitute or complement the existing modern
medications to ameliorate renal function in diabetes constitute
novel therapeutic strategies for diabetes. Evidence from biomedical
literature suggests that some plant extracts have protective effects
against cardiovascular disease in diabetes.
32
The following sections
evaluate the therapeutic and pharmacological evidence for the use
of some of the medicinal plants and their bioactive phytochemicals
in cardio-renal related diabetic complications, as well as the
potential for nephrotoxicity from other plant extracts.
Natural plants for cardiovascular disease
Several plant extracts with potential therapeutic properties for the
treatment of hypertension and complications such as coronary
heart disease, angina, arrhythmias and congestive heart failure
have been identified.
33-36
Traditional medicinal healers in southern
Africa have used
Helichrysum ceres
S Moore [Asteraceae] to treat
kidney and cardio-respiratory disorders.
37
Recent laboratory studies
suggest that the hypotensive effects of
H ceres
leaf extract in
anaesthetised male Sprague-Dawley rats could in part be attributed
to the extract’s natriuretic and diuretic properties.
38
We reported
that
H ceres
ethanolic leaf extract’s hypotensive effects were elicited
in part by the direct relaxant effects on cardiac and vascular smooth
muscles.
39
The data suggested that lowering of blood pressure
was due to reduced peripheral resistance elicited by the extract’s
vasodilatatory effects on the vascular smooth muscles, mediated
in part via the endothelium-derived factors (EDRF). This suggestion
was corroborated by the observations that
H ceres
leaf extract
elicited potent negative inotropic and chronotropic effects
in vivo
and exhibited vasorelaxant effects in vascular tissue preparations.
We also reported that
Ekebergia capensis
Sparrm (Meliaceae)
leaf extract prevented the development of hypertension in weanling
genetically hypertensive Dahl salt-sensitive (DSS) rats, which
develop hypertension as they age.
19
The
in vivo
reduction in blood
pressure by the extract occurred without significant alterations in
the heart rate, suggesting that the
in vitro
cardiovascular effects
of the extract significantly contributed to the hypotensive effects.
Indeed, studies showed that the hypotensive effect of
E capensis
leaf extract was in part mediated via modulation of total peripheral
resistance of the vascular smooth muscles, as evidenced by the
extract’s elicited dose-dependent vasorelaxations in endothelium-
intact and endothelium-denuded aortic ring preparations. It should
be noted that lanoxin, one of the cardiac glycosides found in a
number of plants, has specific effects on the myocardium.
Kidney function changes in diabetes mellitus
Sustained hyperglycaemia is the main cause of the changes in
kidney function in diabetes mellitus. Hyperglycaemia leads to the
increased formation of advanced glycation end-products (AGEs),
oxidative stress, activation of the polyol pathway and hexosamine
flux, causing inflammation and renal damage.
40
AGEs result in the
increased production of extracellular matrix proteins in endothelial
cells, mesangial cells and macrophages in the kidney.
41
Additionally,
AGEs have been shown to reduce matrix protein flexibility through
cross-link formation of the extracellular matrix proteins, leading to
an abnormal interaction with other matrix components.
41
Irrespective of all the other structural and functional changes,
the mesangial alterations appear to be the main cause of declining
renal function in experimental diabetic animal models.
42
For
example, hyperfiltration, which occurs in the early stages of DN
has been attributed to increased mesangial production of vascular
permeability factors in response to stretching.
43
The subsequent
decline in glomerular filtration rate (GFR) as nephropathy progresses
may be due to expansion of the mesangial matrix, which compresses
the glomerular capillaries, thereby reducing the filtration surface
area and impairing the mechanism that maintains the normal
glomerular capillary hydrostatic pressure.
42
The fall in GFR also
reduces the sodium load delivered to the macula densa cells,
resulting in enhanced tubulo-glomerular feedback (TGF).
44
In turn
angiotensin II production increases due to hyper-activation of the
renin–angiotensin–aldosterone system,
45
causing more reabsorption
of sodium and an increase in systemic blood pressure.
The accumulation of AGEs can be prevented by antioxidants
such as flavonoids or by preventing the glucose-dependent
formation of intermediate products (Amadori, Schiff bases or
Milliard products). Indeed, blocking or deleting AGEs’ receptor
(
RAGE) in experimental animals reversed atherosclerosis.
46
Amino
guanidine and pyridoxamine, AGEs formation inhibitors, had reno-
protective effects in diabetic animals.
47,48
Furthermore, inhibition
of AGEs effects could be achieved through breaking of the AGEs
cross links by drugs such as alagebrium or inhibition of AGE signal
transduction.
48
