Oxidative Stress and Diabetic Kidney Disease

Stanton, Robert C.

doi:10.1007/s11892-011-0196-9

Cited by 104 publications

(103 citation statements)

References 57 publications

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“…In animal models, antioxidants have been shown to be effective in treating DN (21,22). In combination with the current human data showing an independent association between bilirubin and renal outcome, we speculate that treatments intended to slightly raise bilirubin levels might have a beneficial effect on progression of nephropathy in patients with type 2 diabetes and low bilirubin levels.…”

Section: Discussionsupporting

confidence: 58%

Bilirubin and Progression of Nephropathy in Type 2 Diabetes: A Post Hoc Analysis of RENAAL With Independent Replication in IDNT

et al. 2014

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Bilirubin, a potent endogenous antioxidant, was found to protect against the development of diabetic nephropathy (DN) in rodents. In humans, cross-sectional studies found an inverse relation between bilirubin and DN. We prospectively investigated whether bilirubin is associated with progression of DN toward end-stage renal disease (ESRD). To this end, we performed a post hoc analysis in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial with independent replication in the Irbesartan Diabetic Nephropathy Trial (IDNT). Subjects with type 2 diabetes and nephropathy with alanine aminotransferase, aspartate aminotransferase (AST), and bilirubin levels <1.5 times the upper limit of normal were included. The renal end point was defined as the composite of confirmed doubling of serum creatinine or ESRD. Bilirubin was inversely associated with the renal end point in RENAAL independent of age, sex, race, BMI, smoking, total cholesterol, diastolic blood pressure, HbA1c, treatment, estimated glomerular filtration rate, albumin-to-creatinine ratio, and AST. These results were confirmed in IDNT. This study indicates an independent inverse association of bilirubin with progression of nephropathy in RENAAL and IDNT. These data suggest a protective effect of bilirubin against progression of nephropathy in type 2 diabetes. The well-established role of bilirubin as an antioxidant is a potential explanation for the findings.

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Section: Discussionsupporting

confidence: 58%

Bilirubin and Progression of Nephropathy in Type 2 Diabetes: A Post Hoc Analysis of RENAAL With Independent Replication in IDNT

et al. 2014

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“…32 There is a strong biologic rationale for inflammation, oxidative stress, and fibrosis, to be critical risk factors for renal disease progression in DKD. [33][34][35] Experimental research has shown that PTF diminishes renal tissue damage through beneficial anti-inflammatory, antioxidant, and antifibrotic effects, 17,36,37 resulting in attenuation of kidney disease progression. This outcome is maximized after combination with RAS blockers.…”

Section: Discussionmentioning

confidence: 99%

Effect of Pentoxifylline on Renal Function and Urinary Albumin Excretion in Patients with Diabetic Kidney Disease

Navarro‐González

Mora‐Fernández

Fuentes

et al. 2015

Journal of the American Society of Nephrology

185

130

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Diabetic kidney disease (DKD) is the leading cause of ESRD. We conducted an open-label, prospective, randomized trial to determine whether pentoxifylline (PTF), which reduces albuminuria, in addition to renin-angiotensin system (RAS) blockade, can slow progression of renal disease in patients with type 2 diabetes and stages 3-4 CKD. Participants were assigned to receive PTF (1200 mg/d) (n=82) or to a control group (n=87) for 2 years. All patients received similar doses of RAS inhibitors. At study end, eGFR had decreased by a mean6SEM of 2.160. patients with a rate of eGFR decline greater than the median rate of decline (0.16 ml/min per 1.73 m 2 per month) was lower in the PTF group than in the control group (33.3% versus 68.2%; P,0.001). Percentage change in urinary albumin excretion was 5.7% (95% CI, 20.3% to 11.1%) in the control group and 214.9% (95% CI, 220.4% to 29.4%) in the PTF group (P=0.001). Urine TNF-a decreased from a median 16 ng/g (interquartile range, 11-20.1 ng/g) to 14.3 ng/g (interquartile range, 9.2-18.4 ng/g) in the PTF group (P,0.01), with no changes in the control group. In this population, addition of PTF to RAS inhibitors resulted in a smaller decrease in eGFR and a greater reduction of residual albuminuria. 26: 220-229, 201526: 220-229, . doi: 10.1681 Diabetic kidney disease (DKD) is the most frequent cause of CKD, and ESRD in type 2 diabetes is considered a medical catastrophe. 1 Strong evidence supports the blockade of the renin-angiotensin system (RAS), most commonly with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptors blockers (ARBs), as an established standard of care in these patients to reduce the risk of developing ESRD. 2 However, these therapies do not provide complete renal protection, 3 and diabetic patients continue to show a high renal risk, which is positively associated with residual albuminuria. 4 Unfortunately, recent studies evaluating new strategies to delay the progression of diabetic nephropathy (DN) have had little success. Trials with pyridoxamine or sulodexide failed to detect a renoprotective effect in patients with type 2 diabetes and renal impairment. 5,6 Meanwhile, studies with the endothelin antagonist avosentan, 7 J Am Soc Nephrol

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“…1 Our recent studies demonstrated that NADPH oxidase-derived ROS production-mediated c-Src kinase activation was an upstream mediator of EGFR activation in renal proximal tubular epithelial cells in response to chronic angiotensin II treatment. 15 A recent study also indicated that inhibition of c-Src kinase prevented progression of diabetic nephropathy.…”

Section: Ros-mediated Podocyte C-src and Egfr/erk Phosphorylationmentioning

confidence: 96%

“…In the United States, diabetic kidney disease is now the major cause of end stage kidney disease 1 and increases the rate of other complications, such as cardiovascular disease. 2 Twenty to forty percent of all patients with diabetes will develop some form of kidney disease during their life.…”

mentioning

confidence: 99%

EGF Receptor Deletion in Podocytes Attenuates Diabetic Nephropathy

Chen¹,

Chen

Harris

2015

Journal of the American Society of Nephrology

113

114

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The generation of reactive oxygen species (ROS), particularly superoxide, by damaged or dysfunctional mitochondria has been postulated to be an initiating event in the development of diabetes complications. The glomerulus is a primary site of diabetic injury, and podocyte injury is a classic hallmark of diabetic glomerular lesions. In streptozotocin-induced type 1 diabetes, podocyte-specific EGF receptor (EGFR) knockout mice (EGFR podKO ) and their wild-type (WT) littermates had similar levels of hyperglycemia and polyuria, but EGFR podKO mice had significantly less albuminuria and less podocyte loss compared with WT diabetic mice. Furthermore, EGFR podKO diabetic mice had less TGF-b1 expression, Smad2/3 phosphorylation, and glomerular fibronectin deposition. Immunoblotting of isolated glomerular lysates revealed that the upregulation of cleaved caspase 3 and downregulation of Bcl2 in WT diabetic mice were attenuated in EGFR podKO diabetic mice. Administration of the SOD mimetic mito-tempol or the NADPH oxidase inhibitor apocynin attenuated the upregulation of p-c-Src, p-EGFR, p-ERK1/2, p-Smad2/3, and TGF-b1 expression and prevented the alteration of cleaved caspase 3 and Bcl2 expression in glomeruli of WT diabetic mice. High-glucose treatment of cultured mouse podocytes induced similar alterations in the production of ROS; phosphorylation of c-Src, EGFR, and Smad2/3; and expression of TGF-b1, cleaved caspase 3, and Bcl2. These alterations were inhibited by treatment with mito-tempol or apocynin or by inhibiting EGFR expression or activity. Thus, results of our studies utilizing mice with podocyte-specific EGFR deletion demonstrate that EGFR activation has a major role in activating pathways that mediate podocyte injury and loss in diabetic nephropathy.

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Oxidative Stress and Diabetic Kidney Disease

Cited by 104 publications

References 57 publications

Bilirubin and Progression of Nephropathy in Type 2 Diabetes: A Post Hoc Analysis of RENAAL With Independent Replication in IDNT

Bilirubin and Progression of Nephropathy in Type 2 Diabetes: A Post Hoc Analysis of RENAAL With Independent Replication in IDNT

Effect of Pentoxifylline on Renal Function and Urinary Albumin Excretion in Patients with Diabetic Kidney Disease

EGF Receptor Deletion in Podocytes Attenuates Diabetic Nephropathy

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