Effects of Spironolactone and Losartan on Diabetic Nephropathy in a Type 2 Diabetic Rat Model

Abstract

BackgroundWhile there is an evidence that the anti-inflammatory properties of spironolactone can attenuate proteinuria in type 2 diabetes, its effects on vascular endothelial growth factor (VEGF) expression in diabetic nephropathy have not been clearly defined. In this study, we examined the effects of spironolactone, losartan, and a combination of these two drugs on albuminuria, renal VEGF expression, and inflammatory and oxidative stress markers in a type 2 diabetic rat model.MethodsThirty-three Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats were divided into four groups and treated with different medication regimens from weeks 25 to 50; OLETF diabetic controls (n=5), spironolactone-treated (n=10), losartan-treated (n=9), and combination of spironolactone- and losartan-treated (n=9).ResultsAt week 50, the albumin-to-creatinine ratio was significantly decreased in the losartan and combination groups compared to the control OLETF group. No decrease was detected in the spironolactone group. There was a significant reduction in renal VEGF, transforming growth factor (TGF)-β, and type IV collagen mRNA levels in the spironolactone- and combination regimen-treated groups. Twenty-four hour urine monocyte chemotactic protein-1 levels were comparable in all four groups but did show a decreasing trend in the losartan and combination regimen groups. Twenty-four hour urine malondialdehyde levels were significantly decreased in the spironolactone- and combination regimen-treated groups.ConclusionThese results suggest that losartan alone and a combined regimen of spironolactone and losartan could ameliorate albuninuria by reducing renal VEGF expression. Also, simultaneous treatment with spironolactone and losartan may have protective effects against diabetic nephropathy by decreasing TGF-β and type IV collagen expression and by reducing oxidative stress in a type 2 diabetic rat model.

Renal Protective Role of Xiexin Decoction with Multiple Active Ingredients Involves Inhibition of Inflammation through Downregulation of the Nuclear Factor-κB Pathway in Diabetic Rats

“…Our data indicated that both exhibited an anti-DN effect, losartan via inhibition of NF- κ B signalling activity and reduction in levels of inflammatory factors, and metformin via improving the glucolipid metabolism disorder, decreasing AGEs, and suppressing expression of RAGE and inflammatory molecules. These results are in agreement with those of previous studies [44–48]. …”

Combination therapy with spironolactone and candesartan protects against streptozotocin-induced diabetic nephropathy in rats

“…Recently, it has been reported that simultaneous treatment with spironolactone and losartan may have protective effects against diabetic nephropathy in a type 2 diabetic rat (Lee et al, 2011). However, the putative role and the underling mechanism(s) by which the combination therapy with spironolactone and candesartan in diabetic nephropathy of type 1 diabetes remain to be fully defined.…”

The use of animal models in diabetes research

“…In addition, the male sex bias is more extreme in these models (Leiter, 2009). These polygenic models have been used in a wide variety of studies that have aimed to reverse the symptoms of type 2 diabetes (Chen et al ., 2009; Fukaya et al ., 2009; Guo et al ., 2010; Mochizuki et al ., 2011; Yoshinari and Igarashi, 2011), understand more about the interplay of obesity and glucose homeostasis (Kluth et al ., 2011) (Jurgens et al ., 2007) or study diabetic complications (Cheng et al ., 2007; Fang et al ., 2010; Buck et al ., 2011; Lee et al ., 2011a).…”

“…The final stage is characterized by islets becoming fibrotic and become replaced by connective tissue (Kawano et al ., 1994). These rats also exhibit renal complications (Lee et al ., 2011a).…”