Association analysis of ADPRT1, AKR1B1, RAGE, GFPT2 and PAI-1 gene polymorphisms with chronic renal insufficiency among Asian Indians with type-2 diabetes

<p>Abstract</p> <p>Background</p> <p>To determine association of nine single nucleotide polymorphisms (SNPs) in ADP ribosyltransferase-1 (ADPRT1), aldo-keto reductase family 1 member B1 (AKR1B1), receptor for advanced glycation end-products (RAGE), glutamine:fructose-6-phosphate amidotransferase-2 (GFPT2), and plasminogen activator inhibitor-1 (PAI-1) genes with chronic renal insufficiency (CRI) among Asian Indians with type 2 diabetes; and to identify epistatic interactionss between genes from the present study and those from renin-angiotensin-aldosterone system (RAAS), and chemokine-cytokine, dopaminergic and oxidative stress pathways (previously investigated using the same sample set).</p> <p>Methods</p> <p>Type 2 diabetes subjects with CRI (serum creatinine ≥3.0 mg/dl) constituted the cases (n = 196), and ethnicity and age matched individuals with diabetes for a duration of ≥ 10 years, normal renal functions and normoalbuminuria recruited as controls (n = 225). Allelic and genotypic constitution of 10 polymorphisms (SNPs) from five genes namely- <it>ADPRT1</it>, <it>AKR1B1, RAGE, GFPT2 </it>and <it>PAI-1 </it>with diabetic CRI was investigated. The genetic associations were evaluated by computation of odds ratio and 95% confidence interval. Multiple logistic regression analysis was carried out to correlate various clinical parameters with genotypes, and to study epistatic interactions between SNPs in different genes.</p> <p>Results</p> <p>Single nucleotide polymorphisms -429 T>C in <it>RAGE </it>and rs7725 C>T SNP in 3' UTR in <it>GFPT2 </it>gene showed a trend towards association with diabetic CRI. Investigation using miRBase statistical tool revealed that rs7725 in <it>GFPT2 </it>was a perfect target for predicted miRNA (hsa miR-378) suggesting the presence of the variant 'T' allele may result in an upregulation of GFPT2 contributing to diabetic renal complication. Epistatic interaction between SNPs in transforming growth factor <it>TGF-β1 </it>(investigated using the same sample set and reported elsewhere) and <it>GFPT2 </it>genotype was observed.</p> <p>Conclusions</p> <p>Association of SNPs in <it>RAGE </it>and <it>GFPT2 </it>suggest that the genes involved in modulation of oxidative pathway could be major contributor to diabetic chronic renal insufficiency. In addition, GFPT2 mediated overproduction of TGF-β1 leading to endothelial expansion and thereby CRI seems likely, suggested by our observation of a significant interaction between GFPT2 with TGF-β1 genes. Further, identification of predicted miRNA targets spanning the associated SNP in <it>GFPT2 </it>implicates the rs7725 SNP in transcriptional regulation of the gene, and suggests <it>GFPT2 </it>could be a relevant target for pharmacological intervention. Larger replication studies are needed to confirm these observations.</p

Renal accumulation and clearance of advanced glycation end-products in type 2 diabetic nephropathy: effect of angiotensin-converting enzyme and vasopeptidase inhibition

Aims/hypothesis: Renal accumulation of AGEs may contribute to the progression of diabetic nephropathy. We evaluated the effect of ramipril (a pure ACE inhibitor) and AVE7688 (a dual inhibitor of ACE and neutral endopeptidase) on renal accumulation of the advanced glycation end-product (AGE) 3-deoxyglucosone-imidazolone, carboxymethyllysine (CML) and pentosidine, and on clearance of CML in type 2 diabetes. \ud \ud Methods: Male Zucker diabetic fatty rats (ZDF, Gmi-fa/fa) rats were treated from age 10 to 37 weeks with ramipril (1 mg·kg−1·day−1), AVE7688 (45 mg·kg−1·day−1) or without drug. Ramipril and AVE7688 reduced albuminuria by 30 and 90%, respectively. \ud \ud Results: ZDF rats showed increased renal accumulation of the AGE subtypes 3-deoxyglucosone-imidazolone, pentosidine and CML by about 40, 55 and 55%, respectively compared with heterozygous, non-diabetic control animals at the age of 37 weeks. AVE7688 but not ramipril attenuated the renal accumulation of 3-deoxyglucosone-imidazolone, pentosidine and CML and improved CML clearance in ZDF rats. During glycation reactions in vitro, AVE7688 also demonstrated potent chelating activity and inhibited metal-catalysed formation of pentosidine and CML. \ud \ud Conclusions/interpretation: Improved AGE clearance and direct inhibition of AGE formation by chelation may contribute to reduced accumulation of renal AGEs and to the nephroprotective effects of vasopeptidase inhibition in type 2 diabetes

Effects of Diabetes-Induced Hyperglycemia in the Heart: Biochemical and Structural Alterations

Hyperglycemia (HG) plays a major role in the development of diabetes mellitus (DM) and its complications. HG induces numerous maladaptations at the cellular level and moreover it is an independent risk factor to worsen cardiac performance and cell survival. The heart is a major target organ for damage with hyperglycemia. Alterations as a result of HG can lead to the development of a diabetic cardiomyopathy, resulting in changes to cardiac structure and function. Mechanisms damaging the heart are similar to those that damage the vasculature, but are more widespread in the myocardium. Four major pathways are implicated in HG-induced cardiac and vascular damage, including increases in advanced glycation end products (AGEs), enhanced hexosamine and polyol flux, and activation of classical isoforms of protein kinase C (PKC). These changes lead to abnormalities such as increased ventricular stiffness, cardiac fibrosis, derangement in cellular calcium ion homeostasis, and reduced myocyte contractility, resulting in heart failure (HF) over time. These pathways reflect upon a single HG-induced process of overproduction of superoxide by the mitochondrial electron-transport chain, which is responsible for the changes occurring in the heart. This chapter discusses the HG-induced pathways, focusing on their effects on the structure of the diabetic heart, as well as examining the downstream signaling whereby oxidative stress leads to myocardial fibrosis and impaired contractile function. In addition, this review highlights the role of endothelin-1 (ET-1) in endothelial dysfunction and the effects of humoral factors, angiotensin II and transforming growth factor-β, in evoking multiple signaling pathways in cardiac fibroblasts or fibrosis that leads to cardiac remodelling. How these signaling pathways mediated by HG contribute to the pathophysiological alterations in the heart is also discussed in this review