Heme Oxygenase-2 Deficiency Contributes to Diabetes-Mediated Increase in Superoxide Anion and Renal Dysfunction

Goodman, Alvin I.; Chander, Praveen N.; Rezzani, Rita; Schwartzman, Michal Laniado; Regan, Raymond F.; Rodella, Luigi Fabrizio; Türkseven, Saadet; Lianos, Elias A.; Dennery, Phyllis A.; Abraham, Nader G.

doi:10.1681/asn.2004121082

Cited by 71 publications

(69 citation statements)

References 68 publications

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“…In addition, HO-2, which contributes the bulk of HO activity in the unstressed kidney, was also suspected to play a protective role in the animal kidney models. 29,30 However, the association between the HO-2 gene polymorphism and kidney disease in humans is still obscure.…”

Section: Discussionmentioning

confidence: 99%

Length Polymorphism in Heme Oxygenase-1 and Risk of CKD among Patients with Coronary Artery Disease

Chen

Kuo

Hung

et al. 2014

Journal of the American Society of Nephrology

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The length polymorphism of guanosine thymidine dinucleotide repeats in the heme oxygenase-1 gene promoter is associated with cardiovascular events and mortality in high-risk populations. Experimental data suggest that heme oxygenase-1 protects against kidney disease. However, the association between this polymorphism and long-term risk of CKD in high-risk patients is unknown. We analyzed the allelic frequencies of guanosine thymidine dinucleotide repeats in the heme oxygenase-1 gene promoter in 386 patients with coronary artery disease recruited from January 1999 to July 2001 and followed until August 31, 2012. The S allele represents short repeats (,27), and the L allele represents long repeats ($27). The primary renal end points consisted of sustained serum creatinine doubling and/or ESRD requiring long-term RRT. The secondary end points were major adverse cardiovascular events and mortality. At the end of study, the adjusted hazard ratios (95% confidence intervals) for each L allele in the additive model were 1.99 (1.27 to 3.14; P=0.003) for the renal end points, 1.70 (1.27 to 2.27; P,0.001) for major adverse cardiovascular events, and 1.36 (1.04 to 1.79; P=0.03) for mortality. With cardiac events as time-dependent covariates, the adjusted hazard ratio for each L allele in the additive model was 1.91 (1.20 to 3.06; P=0.01) for the renal end points. In conclusion, a greater number of guanosine thymidine dinucleotide repeats in the heme oxygenase-1 gene promoter is associated with higher risk for CKD, cardiovascular events, and mortality among patients with coronary artery disease.

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Section: Discussionmentioning

confidence: 99%

Length Polymorphism in Heme Oxygenase-1 and Risk of CKD among Patients with Coronary Artery Disease

Chen

Kuo

Hung

et al. 2014

Journal of the American Society of Nephrology

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“…Recent study reveals that expression level and polymorphism in HO-1 gene promoter is associated with the prevalence of type 2 DM ). In addition to HO-1, HO-2 is known to have a cytoprotective role in the diabetic state (Goodman et al 2006). Second, this role is interpreted to be one component of the biliverdin reductase (BVR) cycle.…”

Section: Discussionmentioning

confidence: 99%

High Serum Bilirubin Is Associated with the Reduced Risk of Diabetes Mellitus and Diabetic Nephropathy

Han

Chae

et al. 2010

Tohoku J. Exp. Med.

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“…In addition to iron recycling, there is evidence for participation of HO-2 in an oxygen-sensing mechanism (Adachi et al 2004;Shibahara et al 2007). Intriguingly, a large body of circumstantial evidence, including human genetic variant association (Shibahara 2003;Bao et al 2010), suggests a potential role for these enzymes of heme catabolism in the protection against the development of a range of chronic diseases, including type-2 diabetes, obesity and oxidative damage, resulting from hyperglycemic conditions, known as glucose toxicity (Goodman et al 2006;Ndisang et al 2009;Sodhi et al 2009;Hosick and Stec 2011). A lack of direct evidence has made the heme catabolism-diabetes link speculative.…”

Section: Heme Oxygenase-1 and Heme Oxygenase-2mentioning

confidence: 99%

“…Thus, HO-1 induction is viewed as the first line cellular defense mechanism the body utilizes to protect against the development of chronic oxidative stress-related diseases. This has been an area of intense research and considerable advances have been achieved, at least in experimental disease models (Goodman et al 2006;Ndisang et al 2009;Sodhi et al 2009;Hosick and Stec 2011). For example, in the Goto-Kakizaki rats, a model for hyperglycemia and insulin resistance without obesity (Goto et al 1976), induction of HO-1 causes a reduction in fasting blood glucose levels and prevents a rise in blood glucose in post absorptive state (Ndisang et al 2009).…”

Section: Human Pancreatic Ductal Epithelial Cells (Hpde)mentioning

confidence: 99%

“…A HO-2 knockout mouse reproduces offspring that undergo normal development to adulthood, but develops the symptomatic spectrum of human type-2 diabetes; hyperglycemia, increased fat deposition, insulin resistance and hypertension with aging (Goodman et al 2006;Sodhi et al 2009;Li et al 2012). Normal fertility and normal development in HO-2 knockout mice suggests that HO-1 could compensate for HO-2 functions such as iron recycling, antiinflammation and anti-oxidative stress.…”

Section: Novel Functions Of Ho-2mentioning

confidence: 99%

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Emerging Roles of Cadmium and Heme Oxygenase in Type-2 Diabetes and Cancer Susceptibility

Satarug

2012

Tohoku J. Exp. Med.

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Many decades after an outbreak of severe cadmium poisoning, known as Itai-itai disease, cadmium continues to pose a significant threat to human health worldwide. This review provides an update on the effects of this environmental toxicant cadmium, observed in numerous populations despite modest exposure levels. In addition, it describes the current knowledge on the link between heme catabolism and glycolysis. It examines novel functions of heme oxygenase-2 (HO-2) that protect against type 2-diabetes and obesity, which have emerged from diabetic/obese phenotypes of the HO-2 knockout mouse model. Increased cancer susceptibility in type-2 diabetes has been noted in several large cohorts. This is a cause for concern, given the high prevalence of type-2 diabetes worldwide. A lifetime exposure to cadmium is associated with pre-diabetes, diabetes, and overall cancer mortality with sex-related differences in specific types of cancer. Liver and kidney are target organs for the toxic effects of cadmium. These two organs are central to the maintenance of blood glucose levels. Further, inhibition of gluconeogenesis is a known effect of heme, while cadmium has the propensity to alter heme catabolism. This raises the possibility that cadmium may mimic certain HO-2 deficiency conditions, resulting in diabetic symptoms. Intriguingly, evidence has emerged from a recent study to suggest the potential interaction and co-regulation of HO-2 with the key regulator of glycolysis: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4). HO-2 could thus be critical to a metabolic switch to cancer-prone cells because the enzyme PFKFB and glycolysis are metabolic requirements for cell proliferation and resistance to apoptosis.

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Heme Oxygenase-2 Deficiency Contributes to Diabetes-Mediated Increase in Superoxide Anion and Renal Dysfunction

Cited by 71 publications

References 68 publications

Length Polymorphism in Heme Oxygenase-1 and Risk of CKD among Patients with Coronary Artery Disease

Length Polymorphism in Heme Oxygenase-1 and Risk of CKD among Patients with Coronary Artery Disease

High Serum Bilirubin Is Associated with the Reduced Risk of Diabetes Mellitus and Diabetic Nephropathy

Emerging Roles of Cadmium and Heme Oxygenase in Type-2 Diabetes and Cancer Susceptibility

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