The efficacy of Aesculus hippocastanum seeds on diabetic nephropathy in a streptozotocin-induced diabetic rat model
Introduction
Diabetic nephropathy (DN) is a common, severe complication of diabetes, developing in 20–40% of diabetic patients [1]. DN is characterized by diffuse glomerulosclerosis and nephrotic syndrome, which are caused by microangiopathy of capillaries in the kidney glomeruli [2].
There are several mechanisms suggested for the pathophysiology of DN. Glomerular hyperfiltration and hyperperfusion represent one mechanism related with high blood glucose levels [3]. Glomerular glucose hyperfiltration causes NaCl loss and results in decreased NaCl presentation to the macula densa. Activated macula densa–mediated feedback mechanisms increase the levels of angiotensin II, which in turn causes glomerular fibrosis and sclerosis with the stimulation of transforming growth factor (TGF)-ß1 (a hypertrophic, prosclerotic cytokine) [4], [5]. Another postulated mechanism for DN is the nonenzymatic glycosylation of tissue proteins resulting from chronic hyperglycemia. The glomerular basal membrane is adversely affected by the formation and deposition of advanced glycation end-products [6]. In addition, these advanced products can alter signal transduction, which can be involved in the pathogenesis of DN via alteration of signaling molecules, such as cytokines, hormones, and free radicals [1].
Another postulated mechanism is chronic hyperglycemia–induced protein kinase C (PKC) activation. This has been associated with alterations in blood flow in renal and glomerular vessels, extracellular matrix expansion, basement membrane thickening, hyperfiltration, enhanced angiogenesis, and excessive apoptosis [7]. PKC activation leads to increased activity of mitogen-activated protein kinase (MAPK) [8]. MAPK activity, PKC activity, and TGF-β1 activation, which is commonly related with oxidative stress and reactive oxygen species (ROS), cause hyperfiltration and glomerular basement membrane thickening [9].
Recent studies have tried to define the pathogenesis of DN via oxidative stress mechanisms. Even before symptoms of diabetes become clinically apparent, hyperglycemia specifically induces oxidative stress [10]. The first event that results in kidney damage is the increased production of reactive oxygen species into the mitochondria due to the oversupply of NADH and FADH2 in the oxidative phosphorylation chain [11]. This is the result of an oversupply of the Krebs’ cycle with pyruvate, which is in turn the result of an increased glucose influx into the cell. The above sequence of events takes place in renal endothelial cells, which are unable to downregulate the glucose transporter-1 despite the hyperglycemic environment [12]. From this event originates a cascade of other detrimental events, such as PKC activation, production of advanced glycation end-products, TGF-β upregulation, and cytosolic NAPDPH consumption. In previous studies, products of lipoxidation in the mesangial matrix was detected via histological analysis of human kidney biopsy specimens [13], [14].
The seeds of the Aesculus hippocastanum (AH) plant (horse chestnut) are used as a drug to treat venous disorders, such as varicose veins, phlebitis, leg ulcers, and hemorrhoids. AH is an astringent and anti-inflammatory plant that helps to decrease the symptoms of certain illnesses, such as arthritis, strains, and tendonitis [15], [16]. Recent studies have shown that AH seeds can decrease the oxidative stress and anti-inflammation effects resulting from decreased levels of cytokines like tumor necrosis factor (TNF)-α and interleukin (IL)-1β in different tissues [17], [18], [19].
In this study, we hypothesized that AH seeds may have preventive effects on oxidative stress and TGF-β-related DN in streptozotocin (STZ)-induced DN in rats.
Section snippets
Animals
Approval for all procedures in the experiment was received from the Ege University Animal Research Ethics Committee. In the study, we used 21 male Sprague Dawley rats. The rats weighed 200–220 g. The animals were fed with standard rat food pellets (Abalim®, Abalioglu Food Inc., Denizli, Turkey) ad libitum and kept in cages with standard laboratory conditions. Animals with blood glucose levels higher than 120 mg/ml were not included in the experiment.
Suspension of A. hippocastanum seeds
In the study, Venotrex® tablets (Abdi Ibrahim,
Results
Histopathological and immunohistochemical examinations of renal tissues are given in Fig. 1. The results of the analysis of the glomerular area (% of control), severity of sclerosis, fibronectin immunoexpression (percent), and levels of MDA, TGF-β, proteinuria, BUN, creatinine, and blood glucose are given in Table 1.
In histopathological and immunohistochemical examinations of renal tissues, a thickening of the glomerular basement membrane and an increase in the mesangial matrix were seen in the
Discussion
In the study, we attempted to prevent STZ-induced DN through the administration of AH seeds in rats. The results showed that AH seeds could prevent the development of STZ-induced DN in rats.
In the literature, when AH seeds were systemically administered to experimental animals, antioxidant effects were shown in different tissues like the kidneys, liver, ileum [17], [18], [19], [28], [29]. In our study, we showed the powerful antioxidant effects of AH seeds on MDA measurements. In addition, AH
Conflict of interest
None of the authors has a conflict of interest to declare.
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