Formononetin attenuates kidney damage in type 2 diabetic rats
Introduction
Diabetic nephropathy (DN) is the most frequently observed vascular complication in approximately 40% of patients suffering from type 2 diabetes [1]. Long lasting kidney diseases and end stage renal failure are the two foremost infirmity observed in the last stage of untreated nephropathy [2]. Diabetic nephropathy represented by glomerulosclerosis, tubular atrophy and interstitial fibrosis, which results into constant decline in glomerular filtration rate [3]. DN is also increases risk of hypertension and cardiovascular complications in diabetics [4]. Mutigenetic factors are involved in development of diabetic nephropathy. However hyperglycemia and associated oxidative stress plays pivotal role to produce vascular damage and alteration in hemodynamic changes such as microalbuminuria, glomerular hyperfiltration and shear stress [5,6]. Hyperglycemia, dyslipidemia, systemic and glomerular hypertension are the key factors of oxidative stress in DN. Oxidative stress generated owing to hyperglycemia and hyperlipidemia affects entire glomerular filtration barrier. Initially, it affects the interaction of endothelial cells with podocytes and glycocalyx layer followed by extracellular matrix deposition and alters the cellular function [7]. Reactive oxidative species also disturb cellular function in kidney by alternating function of various transcription factors [6]. Evidence shows that excessive generation of reactive oxidative species control the activity of SIRT1 in kidney tissue (silent information regulator 2) [8]. In diabetic nephropathy increased oxidative stress causes SIRT1 down regulation in proximal tubule and leads to epigenetic changes in podocytes which is reflected in the form of albuminuria in diabetic patients [9].
Formononetin is an isoflavonoids type of phytoestrogen found in soy and other legume plants. Formononetin is known for its cardioprotective and anti-hyperlipidemic effect [10]. It has also been reported to reduced generation of reactive oxygen species and have significant antioxidant potential [11]. Formononetin has also been used as one of the ingredient of polyhedral formulation for management nephropathy [12]. Recent report shows that formononetin provides anti-inflammatory effect via inhibiting HMGB1 release. In the same study, it has also been reported that inhibition of HMGB1 release is mainly because of up regulation of SIRT1 which leads to reduction in acetylation of HMGB1 [13]. Furthermore, we have reported that formononetin reduces hyperglycemia, improves insulin sensitivity in type 2 diabetic rat along with increased expression of SIRT1 in pancreas [14]. However, there are no systematic study reports available for its effect in diabetic nephropathy. Thus, based on the outcome of our previous study of formononetin treatment in type 2 diabetes mellitus, we designed present study to evaluate the effect on formononetin regimen in type 2 diabetic nephropathy.
Section snippets
Ethics statement
The animals experiment was carried out with the approval of Institutional Animal Ethics Committee.
Experimental animals
Sprague-Dawely rats (Male) were purchased from National Institute of Biosciences, Pune, India. The animals were housed at a temperature (22 ± 2 °C) and humidity (40–60%) controlled area with 12/12 h light-dark cycle. Acclimatization of experimental animals was done for one week before starting the experiment.
Induction of type 2 diabetes mellitus
Type 2 diabetes mellitus was induced in the rats using high fat diet + low dose of
Effect of formononetin on body weight and renal hypertrophy
The effect of formononetin treatment on body weight and renal hypertrophy was measured after sixteen week treatment. As shown in Fig. 1a the average body weight (205.7 ± 6.922) of diabetic animals decreased significantly as compare to the average weight of normal (457.5 ± 14.40) and high fat diet (443.0 ± 11.99) fed animals. Treatment with all doses of formononetin showed increase in body weight when compared with diabetic animals at significant level.
The effect of formononetin treatment on
Discussion
The current study was centered on hypothesis that increase in SIRT1 expression can reduce insulin resistance, oxidative stress and maintain normal lipid profile which is considered as major factor for the development of nephropathy in type 2 diabetic conditions.
The development of nephropathy in type 2 diabetic rats was confirmed by hyperglycemia, insulin resistance, hypertriglyceridemia, hypercholesterolemia, increased concentration of plasma creatinine and BUN, increased renal hypertrophy,
Conclusion
The outcome of the present study indicates that increase in expression of SIRT1 by formononetin could reduce the risk of nephropathy in type 2 diabetes. Thus formononetin would be considered as a new therapeutic agent for type 2 diabetic nephropathy in future.
Conflict of interest
None.
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