Ginger extract diminishes chronic fructose consumption-induced kidney injury through suppression of renal overexpression of proinflammatory cytokines in rats

Abstract

Background: The metabolic syndrome is associated with an increased risk of development and progression of chronic kidney disease. Renal inflammation is well known to play an important role in the initiation and progression of tubulointerstitial injury of the kidneys. Ginger, one of the most commonly used spices and medicinal plants, has been demonstrated to improve diet-induced metabolic abnormalities. However, the efficacy of ginger on the metabolic syndrome-associated kidney injury remains unknown. This study aimed to investigate the impact of ginger on fructose consumption-induced adverse effects in the kidneys.

Methods: The fructose control rats were treated with 10% fructose in drinking water over 5 weeks. The fructose consumption in ginger-treated rats was adjusted to match that of fructose control group. The ethanolic extract of ginger was co-administered (once daily by oral gavage). The indexes of lipid and glucose homeostasis were determined enzymatically, by ELISA and/or histologically. Gene expression was analyzed by Real-Time PCR.

Results: In addition to improve hyperinsulinemia and hypertriglyceridemia, supplement with ginger extract (50 mg/kg) attenuated liquid fructose-induced kidney injury as characterized by focal cast formation, slough and dilation of tubular epithelial cells in the cortex of the kidneys in rats. Furthermore, ginger also diminished excessive renal interstitial collagen deposit. By Real-Time PCR, renal gene expression profiles revealed that ginger suppressed fructose-stimulated monocyte chemoattractant protein-1 and its receptor chemokine (C-C motif) receptor-2. In accord, overexpression of two important macrophage accumulation markers CD68 and F4/80 was downregulated. Moreover, overexpressed tumor necrosis factor-alpha, interleukin-6, transforming growth factor-beta1 and plasminogen activator inhibitor (PAI)-1 were downregulated. Ginger treatment also restored the downregulated ratio of urokinase-type plasminogen activator to PAI-1.

Conclusions: The present results suggest that ginger supplement diminishes fructose-induced kidney injury through suppression of renal overexpression of macrophage-associated proinflammatory cytokines in rats. Our findings provide evidence supporting the protective effect of ginger on the metabolic syndrome-associated kidney injury.

Figure 1

Kidney weight (A), the ratios of kidney weight to body weight (B), glomerular tuft area (C) and representative images showing renal histology (hematoxylin and eosin, magnification: 100X, D-G) in rats. The fructose control rats had free access to 10% fructose in their drinking water over 5 weeks, while the consumption of fructose in the ginger (20 or 50 mg/kg)-treated (by gavage daily) rats was adjusted to that of the fructose control rats. The water-control rats had free access to tap water. All values are means ± SEM (n = 6 each group). *P < 0.05.

Figure 2

Damaged tubules characterized by focal cast formation, slough and dilation of tubular epithelial cells in the cortex (A) and outer of stripe (B), and size of proximal and distal tubes in the cortex (C) of kidney in rats. The fructose control rats had free access to 10% fructose in their drinking water over 5 weeks, while the consumption of fructose in the ginger (20 or 50 mg/kg)-treated (by gavage daily) rats was adjusted to that of the fructose control rats. The water-control rats had free access to tap water. All values are means ± SEM (n = 6 each group). *P < 0.05.

Figure 3

Representative images showing tubular damages characterized by focal cast formation, slough and dilation of tubular epithelial cells (with ※, periodic acid-Schiff staining, magnification: 400X) in the cortex of kidney in rats (A-H). The fructose control rats had free access to 10% fructose in their drinking water over 5 weeks, while the consumption of fructose in the ginger (20 or 50 mg/kg)-treated (by gavage daily) rats was adjusted to that of the fructose control rats. The water-control rats had free access to tap water.

Figure 4

The ratio of Masson’s trichrome-stained area to total tissue area in the renal interstitium (A) and representative images showing Masson’s trichrome-stained interstitial collagen deposit (Blue) (magnification: 400×) in the kidney of rats (B-E). The fructose control rats had free access to 10% fructose in their drinking water over 5 weeks, while the consumption of fructose in the ginger (20 or 50 mg/kg)-treated (by gavage daily) rats was adjusted to that of the fructose control rats. The water-control rats had free access to tap water. All values are means ± SEM (n = 6 each group). *P < 0.05.

Figure 5

Renal triglyceride (A) and total cholesterol (B) contents, and representative images showing histology of kidney (C-F, Oil Red O staining, 400X) in rats. The fructose control rats had free access to 10% fructose in their drinking water over 5 weeks, while the consumption of fructose in the ginger (20 or 50 mg/kg)-treated (by gavage daily) rats was adjusted to that of the fructose control rats. The water-control rats had free access to tap water. All values are means ± SEM (n = 6 each group). *P < 0.05.

Figure 6

Renal mRNA expression of monocyte chemotactic protein (MCP)-1 (A), chemokine (C-C motif) receptor (CCR)-2 (B), CD68 (C) and F4/80 (D) in rats. The fructose control rats had free access to 10% fructose in their drinking water over 5 weeks, while the consumption of fructose in the ginger (20 or 50 mg/kg)-treated (by gavage daily) rats was adjusted to that of the fructose control rats. The water-control rats had free access to tap water. mRNA was determined by Real-Time PCR. Levels in water-control rats were assigned a value of 1. All values are means ± SEM (n = 6 each group). *P < 0.05.

Figure 7

Renal mRNA expression of tissue necrosis factor (TNF)-α (A), interleukin (IL)-6 (B), transforming growth factor (TGF)-β1 (C), plasminogen activator inhibitor (PAI)-1 (D), urokinase-type plasminogen activator (uPA) (E) and the ratio of uPA to PAI-1 (F) in rats. The fructose control rats had free access to 10% fructose in their drinking water over 5 weeks, while the consumption of fructose in the ginger (20 or 50 mg/kg)-treated (by gavage daily) rats was adjusted to that of the fructose control rats. The water-control rats had free access to tap water. mRNA was determined by Real-Time PCR. Levels in water-control rats were assigned a value of 1. All values are means ± SEM (n = 6 each group). *P < 0.05.