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Ruscogenin ameliorates diabetic nephropathy by its anti-inflammatory and anti-fibrotic effects in streptozotocin-induced diabetic rat.

Lu HJ, Tzeng TF, Liou SS, Da Lin S, Wu MC, Liu IM - BMC Complement Altern Med (2014)

Bottom Line: Kidneys were isolated for pathology histology, immunohistochemistry, and Western blot analyses.Ruscogenin treatment was found to markedly improve histological architecture in the diabetic kidney.All of the above abnormalities were reversed by ruscogenin treatment, which also decreased the expression of transforming growth factor-β1 and fibronectin in the diabetic kidneys.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Food Science, College of Agriculture, National Pingtung University of Science and Technology, Pingtung County, Taiwan. mcwu@mail.npust.edu.tw.

ABSTRACT

Background: Ruscogenin is a major steroid sapogenin in the traditional Chinese herb Ophiopogon japonicus that have multiple bioactivities. Recent studies have demonstrated that ruscogenin is involved in down-regulation of intercellular adhesion molecule-1 (ICAM-1) and nuclear factor-κB (NF-κB) activation in anti-inflammatory pathways. We hypothesized that ruscogenin protects against diabetic nephropathy (DN) by inhibiting NF-κB-mediated inflammatory pathway. To test this hypothesis, the present study was to examine the effects of ruscogenin in rats with streptozotocin (STZ)-induced DN.

Methods: Diabetes was induced with STZ (60 mg/kg) by intraperitoneal injection in rats. Two weeks after STZ injection, rats in the treatment group were orally dosed with 0.3, 1.0 or 3.0 mg/kg ruscogenin for 8 weeks. The normal rats were chosen as nondiabetic control group. The rats were sacrificed 10 weeks after induction of diabetes. Changes in renal function-related parameters in plasma and urine were analyzed at the end of the study. Kidneys were isolated for pathology histology, immunohistochemistry, and Western blot analyses.

Results: Ruscogenin administration did not lower the levels of plasma glucose and glycosylated hemoglobin in STZ-diabetic rats. Diabetic rats exhibited renal dysfunction, as evidenced by reduced creatinine clearance, blood urea nitrogen and proteinuria, along with marked elevation in the ratio of kidney weight to body weight, that were reversed by ruscogenin. Ruscogenin treatment was found to markedly improve histological architecture in the diabetic kidney. Renal NF-κB activity, as wells as protein expression and infiltration of macrophages were increased in diabetic kidneys, accompanied by an increase in protein content of intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 in kidney tissues. All of the above abnormalities were reversed by ruscogenin treatment, which also decreased the expression of transforming growth factor-β1 and fibronectin in the diabetic kidneys.

Conclusions: Our data demonstrated that ruscogenin suppressed the inflammation and ameliorated the structural and functional abnormalities of the diabetic kidney in rats might be associated with inhibition of NF-κB mediated inflammatory genes expression.

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Effects of treatments on cytokines levels in renal tissues of rats. STZ-diabetic rats treated for eight weeks with ruscogenin (RUS) or rosiglitazone (Rosi). STZ-diabetic rats were dosed by oral gavage once daily for eight weeks with 3 mg/kg RUS (STZ + RUS) or 5 mg/kg RGZ (STZ + Rosi). Normal (normal + Veh) or STZ-diabetic rats receiving vehicle treatment (STZ + Veh) were administered the same volume of vehicle (Veh) used to prepare test medications. Values (mean ± SD) were obtained for each group of 8 animals. aP < 0.05 and bP < 0.01 compared to the values of vehicle-treated normal rats, respectively. cP < 0.05 and dP < 0.01 compared to the values of vehicle-treated STZ-diabetic rats, respectively.
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Figure 3: Effects of treatments on cytokines levels in renal tissues of rats. STZ-diabetic rats treated for eight weeks with ruscogenin (RUS) or rosiglitazone (Rosi). STZ-diabetic rats were dosed by oral gavage once daily for eight weeks with 3 mg/kg RUS (STZ + RUS) or 5 mg/kg RGZ (STZ + Rosi). Normal (normal + Veh) or STZ-diabetic rats receiving vehicle treatment (STZ + Veh) were administered the same volume of vehicle (Veh) used to prepare test medications. Values (mean ± SD) were obtained for each group of 8 animals. aP < 0.05 and bP < 0.01 compared to the values of vehicle-treated normal rats, respectively. cP < 0.05 and dP < 0.01 compared to the values of vehicle-treated STZ-diabetic rats, respectively.

Mentions: Among the many potential pathogenetic mechanisms that are responsible for the development of diabetic kidney disease, an inflammatory mechanism has been suggested to be involved in the development of DN [3]. Macrophages are key inflammatory cells mediating kidney inflammation in experimental and human diabetes. In diabetes, macrophage accumulation and activation are associated with prolonged hyperglycemia, glomerular immune complex deposition, increased chemokine production, and progressive fibrosis [17,18]. Activated macrophages elaborate a host of proinflammatory, profibrotic, and antiangiogenic factors. Using accumulation of ED-1 as a marker of macrophage activation [26], we have demonstrated that increased macrophage activation in the glomeruli of kidney tissue from STZ-diabetic rats (Figure 2). In contrast, kidneys from control rats showed no significant macrophage infiltration (Figure 2). Treatment of STZ-diabetic rats with rosiglitazone or ruscogenin (3.0 mg/kg/day) for eight weeks caused a 33.8 ± 4.6% and 43.4 ± 3.9% reduction of macrophage influx, respectively, relative to that in their vehicle-treated counterparts (Figure 2). The renal expression of inflammatory cytokines such as TNF-α, IL-6 and IL-1β were demonstrated to increase in diabetes, contributing to the development of DN [27]. Along with the effects on macrophages, there was a reduction in the upregulated protein expression of TNF-α, IL-6 and IL-1β from kidneys of STZ-diabetic rats receiving ruscogenin (3.0 mg/kg/day) treatment (Figure 3). Thus, we believe that the anti-inflammatory effects of ruscogenin, through the inhibition of macrophage infiltration, might provide a renoprotective effect in the STZ- diabetic model.


Ruscogenin ameliorates diabetic nephropathy by its anti-inflammatory and anti-fibrotic effects in streptozotocin-induced diabetic rat.

Lu HJ, Tzeng TF, Liou SS, Da Lin S, Wu MC, Liu IM - BMC Complement Altern Med (2014)

Effects of treatments on cytokines levels in renal tissues of rats. STZ-diabetic rats treated for eight weeks with ruscogenin (RUS) or rosiglitazone (Rosi). STZ-diabetic rats were dosed by oral gavage once daily for eight weeks with 3 mg/kg RUS (STZ + RUS) or 5 mg/kg RGZ (STZ + Rosi). Normal (normal + Veh) or STZ-diabetic rats receiving vehicle treatment (STZ + Veh) were administered the same volume of vehicle (Veh) used to prepare test medications. Values (mean ± SD) were obtained for each group of 8 animals. aP < 0.05 and bP < 0.01 compared to the values of vehicle-treated normal rats, respectively. cP < 0.05 and dP < 0.01 compared to the values of vehicle-treated STZ-diabetic rats, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3986976&req=5

Figure 3: Effects of treatments on cytokines levels in renal tissues of rats. STZ-diabetic rats treated for eight weeks with ruscogenin (RUS) or rosiglitazone (Rosi). STZ-diabetic rats were dosed by oral gavage once daily for eight weeks with 3 mg/kg RUS (STZ + RUS) or 5 mg/kg RGZ (STZ + Rosi). Normal (normal + Veh) or STZ-diabetic rats receiving vehicle treatment (STZ + Veh) were administered the same volume of vehicle (Veh) used to prepare test medications. Values (mean ± SD) were obtained for each group of 8 animals. aP < 0.05 and bP < 0.01 compared to the values of vehicle-treated normal rats, respectively. cP < 0.05 and dP < 0.01 compared to the values of vehicle-treated STZ-diabetic rats, respectively.
Mentions: Among the many potential pathogenetic mechanisms that are responsible for the development of diabetic kidney disease, an inflammatory mechanism has been suggested to be involved in the development of DN [3]. Macrophages are key inflammatory cells mediating kidney inflammation in experimental and human diabetes. In diabetes, macrophage accumulation and activation are associated with prolonged hyperglycemia, glomerular immune complex deposition, increased chemokine production, and progressive fibrosis [17,18]. Activated macrophages elaborate a host of proinflammatory, profibrotic, and antiangiogenic factors. Using accumulation of ED-1 as a marker of macrophage activation [26], we have demonstrated that increased macrophage activation in the glomeruli of kidney tissue from STZ-diabetic rats (Figure 2). In contrast, kidneys from control rats showed no significant macrophage infiltration (Figure 2). Treatment of STZ-diabetic rats with rosiglitazone or ruscogenin (3.0 mg/kg/day) for eight weeks caused a 33.8 ± 4.6% and 43.4 ± 3.9% reduction of macrophage influx, respectively, relative to that in their vehicle-treated counterparts (Figure 2). The renal expression of inflammatory cytokines such as TNF-α, IL-6 and IL-1β were demonstrated to increase in diabetes, contributing to the development of DN [27]. Along with the effects on macrophages, there was a reduction in the upregulated protein expression of TNF-α, IL-6 and IL-1β from kidneys of STZ-diabetic rats receiving ruscogenin (3.0 mg/kg/day) treatment (Figure 3). Thus, we believe that the anti-inflammatory effects of ruscogenin, through the inhibition of macrophage infiltration, might provide a renoprotective effect in the STZ- diabetic model.

Bottom Line: Kidneys were isolated for pathology histology, immunohistochemistry, and Western blot analyses.Ruscogenin treatment was found to markedly improve histological architecture in the diabetic kidney.All of the above abnormalities were reversed by ruscogenin treatment, which also decreased the expression of transforming growth factor-β1 and fibronectin in the diabetic kidneys.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Food Science, College of Agriculture, National Pingtung University of Science and Technology, Pingtung County, Taiwan. mcwu@mail.npust.edu.tw.

ABSTRACT

Background: Ruscogenin is a major steroid sapogenin in the traditional Chinese herb Ophiopogon japonicus that have multiple bioactivities. Recent studies have demonstrated that ruscogenin is involved in down-regulation of intercellular adhesion molecule-1 (ICAM-1) and nuclear factor-κB (NF-κB) activation in anti-inflammatory pathways. We hypothesized that ruscogenin protects against diabetic nephropathy (DN) by inhibiting NF-κB-mediated inflammatory pathway. To test this hypothesis, the present study was to examine the effects of ruscogenin in rats with streptozotocin (STZ)-induced DN.

Methods: Diabetes was induced with STZ (60 mg/kg) by intraperitoneal injection in rats. Two weeks after STZ injection, rats in the treatment group were orally dosed with 0.3, 1.0 or 3.0 mg/kg ruscogenin for 8 weeks. The normal rats were chosen as nondiabetic control group. The rats were sacrificed 10 weeks after induction of diabetes. Changes in renal function-related parameters in plasma and urine were analyzed at the end of the study. Kidneys were isolated for pathology histology, immunohistochemistry, and Western blot analyses.

Results: Ruscogenin administration did not lower the levels of plasma glucose and glycosylated hemoglobin in STZ-diabetic rats. Diabetic rats exhibited renal dysfunction, as evidenced by reduced creatinine clearance, blood urea nitrogen and proteinuria, along with marked elevation in the ratio of kidney weight to body weight, that were reversed by ruscogenin. Ruscogenin treatment was found to markedly improve histological architecture in the diabetic kidney. Renal NF-κB activity, as wells as protein expression and infiltration of macrophages were increased in diabetic kidneys, accompanied by an increase in protein content of intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 in kidney tissues. All of the above abnormalities were reversed by ruscogenin treatment, which also decreased the expression of transforming growth factor-β1 and fibronectin in the diabetic kidneys.

Conclusions: Our data demonstrated that ruscogenin suppressed the inflammation and ameliorated the structural and functional abnormalities of the diabetic kidney in rats might be associated with inhibition of NF-κB mediated inflammatory genes expression.

Show MeSH
Related in: MedlinePlus