Document Information


PMID 19056645  (  )
Title Green tea (Camellia sinensis) attenuates nephropathy by downregulating Nox4 NADPH oxidase in diabetic spontaneously hypertensive rats.
Abstract Green tea (GT), through its antioxidant properties, may be useful to treat or prevent human diseases. Because several lines of evidence suggest that oxidative stress contributes to the pathogenesis of diabetic nephropathy, we tested the hypothesis that GT prevents diabetes and hypertension-related renal oxidative stress, attenuating renal injury. Spontaneously hypertensive rats (SHR) with streptozotocin-induced diabetes and nondiabetic SHR were treated daily with tap water or freshly prepared GT (13.3 g/L). After 12 wk, the systolic blood pressure did not differ between treated and untreated nondiabetic or diabetic rats. However, body weight was less (P < 0.05) and glycemia was greater in diabetic SHR rats than in nondiabetic rats. Renal oxidative stress variables such as 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nitrotyrosine expression, NADPH oxidase-dependent superoxide generation, and the expression of renal cortex Nox4 were greater (P < 0.05) in diabetic rats that received water (DW) than in nondiabetic rats that received water (CW). The 8-OHdG and NADPH oxidase-dependent superoxide generation were significantly less in rats treated with GT. Nitrotyrosine and Nox4 expression were significantly less in diabetic rats that received GT (DGT) than in DW. Likewise, the indices of renal injury, albuminuria, and renal expression of collagen IV were significantly greater in DW than in CW. These differences were significantly less in DGT than in DW. GT reestablished the redox state and reduced the indicators of nephropathy without altering glycemia and blood pressure levels in diabetic SHR. These findings suggest that the consumption of GT may ameliorate nephropathy in diabetic hypertensive patients.

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Targets by SciMiner Summary

HUGO ID Symbol Target Name #Occur ActualStr
7891NOX4NADPH oxidase 417Nox4 |
14874NOX5NADPH oxidase, EF-hand calcium binding domain 512nadph oxidase |
2197COL1A1collagen, type I, alpha 18collagen |
2202COL4A1collagen, type IV, alpha 17collagen iv |
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)3gp91phox |
399ALBalbumin3albumin | serum albumin |
6081INSinsulin2insulin |
7876NOS3nitric oxide synthase 3 (endothelial cell)1endothelial nitric oxide synthase |
11416STNstatin1statin |

 


Targets by SciMiner Full list

HUGO ID Symbol Name ActualStr Score FlankingText
7891NOX4NADPH oxidase 4Nox41.7NADPH oxidase-dependent superoxide generation and the expression of renal cortex Nox4 were greater ( P _lt_ 0.05 in diabetic rats that
7891NOX4NADPH oxidase 4Nox41.7Nitrotyrosine and Nox4 expression were significantly less in diabetic rats that received GT
2197COL1A1collagen, type I, alpha 1collagen0.6the indices of renal injury albuminuria and renal expression of collagen IV were significantly greater in DW than in CW
7891NOX4NADPH oxidase 4Nox41.7For instance phosphorothioated antisense oligonucleotides for Nox4 a homolog of the gp91phox subunit of NADPH oxidase inhibits
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)gp91phox0.0instance phosphorothioated antisense oligonucleotides for Nox4 a homolog of the gp91phox subunit of NADPH oxidase inhibits NADPH-dependent ROS generation in the
7891NOX4NADPH oxidase 4Nox41.7the effects of GT on the expression of NADPH oxidase Nox4 which is a major source of ROS production in the
2197COL1A1collagen, type I, alpha 1collagen0.6(an an indicator of oxidative/nitrosative oxidative nitrosative stress-induced protein modifications collagen IV and Nox4 (a a homolog of the gp91phox subunit
7891NOX4NADPH oxidase 4Nox41.7of oxidative/nitrosative oxidative nitrosative stress-induced protein modifications collagen IV and Nox4 (a a homolog of the gp91phox subunit of NADPH oxidase
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)gp91phox0.0modifications collagen IV and Nox4 (a a homolog of the gp91phox subunit of NADPH oxidase by Western blot analysis ( 19
2197COL1A1collagen, type I, alpha 1collagen0.6antibody (1:2000; 1 2000 clone 1A6 Upstate goat anti-type IV collagen antibody (1:500; 1 500 Southern Biotech or rabbit polyclonal anti-Nox4
2197COL1A1collagen, type I, alpha 1collagen0.6show that GT ameliorates the albuminuria and renal accumulation of collagen IV and reduces markers of renal oxidative stress in diabetic
7891NOX4NADPH oxidase 4Nox41.7these beneficial effects apparently involves the downregulation of NADPH oxidase Nox4 expression
7891NOX4NADPH oxidase 4Nox41.7Nox4 a homolog of the gp91phox subunit of NADPH is highly
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)gp91phox0.0Nox4 a homolog of the gp91phox subunit of NADPH is highly expressed in the kidney (
7891NOX4NADPH oxidase 4Nox41.7Overexpression of Nox4 in the kidney of diabetic rats with STZ-induced diabetes may
7891NOX4NADPH oxidase 4Nox41.7( 20 reported that downregulation of Nox4 induced by antisense oligonucleotides completely attenuated oxidative stress in the
7891NOX4NADPH oxidase 4Nox41.7mice ameliorated the albuminuria and renal mesangial expansion by downregulating Nox4
7891NOX4NADPH oxidase 4Nox41.7In agreement with these findings the downregulation of Nox4 by GT completely attenuated oxidative stress and renal injury in
7891NOX4NADPH oxidase 4Nox41.7The molecular mechanism by which GT regulates Nox4 activity remains to be elucidated
7891NOX4NADPH oxidase 4Nox41.7diabetic hypertensive rats by inhibiting oxidative stress through downregulation of Nox4 expression
7891NOX4NADPH oxidase 4Nox41.7SHR that consumed water or GT for 12 wk of Nox4 ( A and nitrotyrosine ( C
7891NOX4NADPH oxidase 4Nox41.7Densitometric analysis of both bands was used to determine the Nox4 actin ratio ( B and nitrotyrosine actin ratio ( D
2197COL1A1collagen, type I, alpha 1collagen0.6SHR that consumed water or GT for 12 wk of collagen IV ( A
2197COL1A1collagen, type I, alpha 1collagen0.6Densitometric analysis of both bands was used to determine the collagen IV B -tubulin ratio presented as arbitrary units (AU) AU
7891NOX4NADPH oxidase 4Nox41.7NADPH-dependent superoxide generation Nox4 expression and oxidative stress markers
7891NOX4NADPH oxidase 4Nox41.7The expression of Nox4 was greater ( P = 0.04 in the DW group
2197COL1A1collagen, type I, alpha 1collagen0.6The urinary AER and the accumulation of kidney collagen IV were used as markers of functional and morphological renal
2197COL1A1collagen, type I, alpha 1collagen0.6Western blotting showed that renal cortical expression of collagen IV was greater ( P = 0.01 in DW rats
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0renal oxidative stress variables such as 8 hydroxy 2' deoxyguanosine 8 ohdg and nitrotyrosine expression nadph oxidase dependent superoxide generation and the expression of renal cortex nox4 were greater p _lt_ 0.05 in diabetic rats that received water dw than in nondiabetic rats that received water cw .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0the 8 ohdg and nadph oxidase dependent superoxide generation were significantly less in rats treated with gt.
2202COL4A1collagen, type IV, alpha 1collagen iv1.0likewise the indices of renal injury albuminuria and renal expression of collagen iv were significantly greater in dw than in cw.
7876NOS3nitric oxide synthase 3 (endothelial cell)endothelial nitric oxide synthase1.0some of these pathways include enhanced activity of the mitochondrial electron transport chain induced by hyperglycemia 12 increased expression and uncoupling of endothelial nitric oxide synthase leading to greater production of superoxide relative to nitric oxide 9 and activation of the reduced forms of nadph 13 15 .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0strategies that reduce superoxide formation via nadph oxidase and/or increase the activity of antioxidant defense systems can attenuate hyperglycemia induced renal injury 18 20 22 .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0for instance phosphorothioated antisense oligonucleotides for nox4 a homolog of the gp91phox subunit of nadph oxidase inhibits nadph dependent ros generation in the renal cortex and reduces glomerular hypertrophy and the expression of renal fibronectin 20 .
6081INSinsulininsulin1.0the administration of epigallocatechin gallate a polyphenol that accounts for ~30% of the dry weight of gt to shr improves endothelial function and insulin sensitivity and reduces blood pressure 24 .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0in addition to explore the underlying molecular mechanisms we examined the effects of gt on the expression of nadph oxidase nox4 which is a major source of ros production in the kidney 20 .
6081INSinsulininsulin1.0diabetic rats received 2 u of long acting insulin novo industry a/s 3 times each week.
399ALBalbuminalbumin1.0body weight plasma glucose systolic blood pressure sbp and albumin excretion rate aer were measured at 0 4 8 and 12 wk.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0nadph oxidase activity.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0nadph oxidase activity was measured by the lucigenin enhanced chemiluminescence method as previously described by gorin et al.
399ALBalbuminserum albumin1.0protein concentrations were measured using the bradford dye binding method 26 with bovine serum albumin as the standard.
2202COL4A1collagen, type IV, alpha 1collagen iv1.0renal cortical homogenates were prepared as described elsewhere 19 and were used to quantify nitrotyrosine an indicator of oxidative/nitrosative stress induced protein modifications collagen iv and nox4 a homolog of the gp91phox subunit of nadph oxidase by western blot analysis 19 .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0 as described elsewhere 19 and were used to quantify nitrotyrosine an indicator of oxidative/nitrosative stress induced protein modifications collagen iv and nox4 a homolog of the gp91phox subunit of nadph oxidase by western blot analysis 19 .
2202COL4A1collagen, type IV, alpha 1collagen iv1.0the results of this study show that gt ameliorates the albuminuria and renal accumulation of collagen iv and reduces markers of renal oxidative stress in diabetic shr.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0the underlying mechanism of these beneficial effects apparently involves the downregulation of nadph oxidase nox4 expression.
11416STNstatinstatin1.0 32 found that the administration of a statin pitavastatin to db/db mice ameliorated the albuminuria and renal mesangial expansion by downregulating nox4.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0figure 1 nadph oxidase activity in renal cortical homogenates from nondiabetic and diabetic shr that consumed water or gt for 12 wk.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0 b mean nadph oxidase activities during the last 5 min were used for comparison among the groups.
2202COL4A1collagen, type IV, alpha 1collagen iv1.0figure 4 representative western blots of the renal cortical expression from nondiabetic and diabetic shr that consumed water or gt for 12 wk of collagen iv a .
2202COL4A1collagen, type IV, alpha 1collagen iv1.0densitometric analysis of both bands was used to determine the collagen iv: b tubulin ratio presented as arbitrary units au b .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0these results indicated that nadph oxidase was the most likely source of superoxide anion.
2202COL4A1collagen, type IV, alpha 1collagen iv1.0the urinary aer and the accumulation of kidney collagen iv were used as markers of functional and morphological renal injury respectively.
2202COL4A1collagen, type IV, alpha 1collagen iv1.0western blotting showed that renal cortical expression of collagen iv was greater p = 0.01 in dw rats than in nondiabetic shr and was reduced to the levels of both nondiabetic groups in the dgt dm x gt; p = 0.03 fig 4 a b .
399ALBalbuminalbumin1.0abbreviations used: 8ohdg 8 hydroxy 2' deoxyguanosine; aer albumin excretion rate; auc area under the curve; cw nondiabetic rats that received water; cgt nondiabetic rats that received daily green tea; dm diabetes mellitus; dw diabetic rats that received water; dgt