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- Zhang, DY, et al.
(author)
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Genetic and functional effects of membrane metalloendopeptidase on diabetic nephropathy development
- 2011
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In: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 34:5, s. 483-490
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Journal article (peer-reviewed)abstract
- <i>Background/Aims:</i> Vasopeptidase as an agent inhibits membrane metalloendopeptidase (MME, also known as neutral endopeptidase). MME is widely distributed in the body and particularly abundant in the kidney. The <i>MME </i>gene is located on chromosome 3q25.1 within a linkage region for diabetic nephropathy (DN). The present study aims to evaluate the genetic and functional effects of MME in the development of DN. <i>Methods:</i> A case-control genetic study of the<i> MME</i> gene in type 1 diabetes (T1D) patients with and without DN (n = 578/599) was performed. All subjects were selected from the Genetics of Kidneys in Diabetes study. Genotyping was performed with TagMan allelic discrimination. <i>Mme </i>mRNA and protein expression levels in kidney tissues of db/db mice at the ages of 5, 12 and 26 weeks were analyzed with TaqMan real-time RT-PCR and Western blot. <i>Results:</i> The haplotype A-C constructed with single nucleotide polymorphisms (SNPs) rs3796268A/G and rs3773885C/T in the <i>MME</i> gene was found to be associated with DN (p = 0.015, OR = 1.33, 95% CI 1.05–1.68) in female T1D patients. Further analyses of renal traits in T1D patients with DN and end-stage renal disease according to the genotypes of SNP rs3773885 indicated that the C allele carriers had higher serum creatinine levels compared to the subjects carrying T allele in both females and males. <i>Mme </i>expression at mRNA and protein levels was upregulated in kidneys of db/db mice at the ages of 12 and 26 weeks (p = 0.017 and <0.001) but not at the age of 5 weeks compared to the controls. <i>Conclusions:</i> The present study provides the first evidence that <i>MME </i>has genetic and biological effects on the development of DN, and suggests that the inhibition of <i>MME </i>expression in the kidney with the agent of vasopeptidase may be a useful therapeutic approach for this disease.
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- Abu Seman, N, et al.
(author)
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Evaluation of the association of plasma pentraxin 3 levels with type 2 diabetes and diabetic nephropathy in a Malay population
- 2013
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In: Journal of diabetes research. - : Hindawi Limited. - 2314-6745 .- 2314-6753. ; 2013, s. 298019-
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Journal article (peer-reviewed)abstract
- Recent reports have demonstrated that elevated plasma long pentraxin 3 (PTX3) levels are associated with cardiovascular and chronic kidney diseases. In the current study, we investigated the plasma PTX3 levels in 296 Malay subjects including the subjects with normal glucose tolerance (NGT) and type 2 diabetes (T2DM) patients with or without DN by using an enzyme-linked immune-sorbent assay. Results showed that in males, plasma PTX3 levels in T2DM patients without DN were lower than that in the subjects with NGT (2.78 versus 3.98 ng/mL;P=0.021). Plasma PTX3 levels in T2DM patients with DN were decreased compared to the patients without DN (1.63 versus 2.78 ng/mL;P=0.013). In females, however, no significant alteration of plasma PTX3 levels among NGT subjects and T2DM patients with and without DN was detected. Furthermore, an inverse correlation between PTX3 and body mass index was found in male subjects with NGT (P=0.012;r=-0.390), but not in male T2DM patients, neither in all females. The current study provided the first evidence that decreased plasma PTX3 levels are associated with T2DM and DN in Malay men and also suggested that PTX3 may have different effects in DN and chronic kidney diseases.
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- Abu Seman, N, et al.
(author)
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Genetic and biological effects of sodium-chloride cotransporter (SLC12A3) in diabetic nephropathy
- 2014
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In: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 40:5, s. 408-416
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Journal article (peer-reviewed)abstract
- <b><i>Background/Aims:</i></b> Solute carrier family 12 member 3 (<i>SLC12A3</i>) encodes a sodium/chloride transporter in kidneys. Previous reports suggest that Arg913Gln polymorphism in this gene is associated with diabetic nephropathy (DN), but the data appear to be inconsistent. Up to now, there is no biological evidence concerning the effects of <i>SLC12A3</i> in DN. In this study, we aim to evaluate the genetic effects of the <i>SLC12A3 </i>gene and its Arg913Gln polymorphism with genetic and functional analyses. <b><i>Methods:</i></b> We genotyped <i>SLC12A3</i> genetic polymorphisms including Arg913Gln in 784 non-diabetes controls and 633 type 2 diabetes (T2D) subjects with or without DN in a Malaysian population and performed a meta-analysis of the present and previous studies. We further analyzed the role of <i>slc12a3</i> in kidney development and progress of DN in zebrafish and db/db mice. <b><i>Results:</i></b> We found that <i>SLC12A3</i> Arg913Gln polymorphism was associated with T2D (p = 0.028, OR = 0.772, 95% CI = 0.612-0.973) and DN (p = 0.038, OR = 0.547, 95% CI = 0.308-0.973) in the Malaysian cohort. The meta-analysis confirmed the protective effects of <i>SLC12A3</i> 913Gln allele in DN (Z-value = -1.992, p = 0.046, OR = 0.792). Furthermore, with knockdown of zebrafish ortholog, <i>slc12a3 </i>led to structural abnormality of kidney pronephric distal duct at 1-cell stage. <i>Slc12a3</i> mRNA and protein expression levels were upregulated in kidneys of db/db mice from 6, 12, and 26 weeks at the age. <b><i>Conclusion:</i></b> The present study provided the first biological and further genetic evidence that <i>SLC12A3</i> has genetic susceptibility in the development of DN, while the minor 913Gln allele in this gene confers a protective effect in the disease. i 2014 S. Karger AG, Basel
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- Ekberg, NR, et al.
(author)
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Protective Effect of the HIF-1A Pro582Ser Polymorphism on Severe Diabetic Retinopathy
- 2019
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In: Journal of diabetes research. - : Hindawi Limited. - 2314-6753 .- 2314-6745. ; 2019, s. 2936962-
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Journal article (peer-reviewed)abstract
- Objective. Hypoxia is central in the pathogenesis of diabetic retinopathy (DR). Hypoxia-inducible factor-1 (HIF-1) is the key mediator in cellular oxygen homeostasis that facilitates the adaptation to hypoxia. HIF-1 is repressed by hyperglycemia contributing by this to the development of complications in diabetes. Recent work has shown that the HIF-1A Pro582Ser polymorphism is more resistant to hyperglycemia-mediated repression, thus protecting against the development of diabetic nephropathy. In this study, we have investigated the effect of the HIF-1A Pro582Ser polymorphism on the development of DR and further dissected the mechanisms by which the polymorphism confers a relative resistance to the repressive effect of hyperglycemia. Research Design and Method. 703 patients with type 1 diabetes mellitus from one endocrine department were included in the study. The degree of retinopathy was correlated to the HIF-1A Pro582Ser polymorphism. The effect of glucose on a stable HIF-1A construct with a Pro582Ser mutation was evaluated in vitro. Results. We identified a protective effect of HIF-1A Pro582Ser against developing severe DR with a risk reduction of 95%, even when adjusting for known risk factors for DR such as diabetes duration, hyperglycemia, and hypertension. The Pro582Ser mutation does not cancel the destabilizing effect of glucose but is followed by an increased transactivation activity even in high glucose concentrations. Conclusion. The HIF-1A genetic polymorphism has a protective effect on the development of severe DR. Moreover, the relative resistance of the HIF-1A Pro582Ser polymorphism to the repressive effect of hyperglycemia is due to the transactivation activity rather than the protein stability of HIF-1α.
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