POLYMORPHISM OF ANGIOTENSIN-CONVERTING ENZYME (rs4340) AND DIABETIC NEPHROPATHY IN CAUCASIANS WITH TYPE 2 DIABETES MELLITUS
Šeruga M, Makuc J,, Završnik M, Cilenšek I, Ekart R, Petrovič D M. Šeruga and J. Makuc contributed equally to this study.
*Corresponding Author: Professor Dr. Daniel Petrovič, M.D., Ph.D., Institute of Histology and Embryology, Faculty of Medicine, University of Ljubljana, Korytkova 2, 1000 Ljubljana, Slovenia. Tel: +386-1-543-7360. Fax: +386-1-543-7361. E-mail: daniel.petrovic@mf.uni-lj.si
page: 29

INTRODUCTION

Type 2 diabetes mellitus (T2DM) is a multifactorial chronic metabolic disease characterized by post-prandial hyperglycemia that causes long-term macrovascular or microvascular complications. Microvascular complications are diabetic nephropathy (DN), neuropathy and diabetic retinopathy (DR) [1,2]. Diabetes mellitus (DM) is the most common cause of chronic kidney disease and end-stage renal disease [1,2]. In the pathogenesis of DN several environmental, genetic, and epigenetic factors are involved in complex interactions [3-5]. In DN, there is a major decrease in glomerular filtration rate (GFR) together with a rise in the excretion of proteins in urine [6]. The pathogenesis of DN is related to uncontrolled or chronic hyperglycemia and is characterized by hypertrophy of glomeruli, hyperperfusion, thickening of basement membranes and glomerular hyperfiltration. There is microalbuminuria and subsequently, progressive glomerulosclerosis, but tubulointerstitial fibrosis may occur, eventually leading to reduction in GFR [1,2]. In progression of DM and its complications, many risk factors are involved, e.g., hypertension, dyslipidemia, smoking, obesity, aging and insulin resistance [7,8]. Clinically, non pharmacological interventions such as strict glycemic and blood pressure control, decrease in smoking and in dietary protein intake, have been shown to slow the progression of DN. The most validated clinical strategy for slowing disease progression is therapeutic targeting of the renin-angiotensin aldesterone system (RAAS) [9,10]. Genetic polymorphisms of the RAAS system may affect the progression of DM and its complications, whereby angiotensinogen, angiotensin receptor and angiotensinconverting enzyme (ACE) gene polymorphisms have been implicated in the pathophysiology of DN [11]. Angiotensin- converting enzyme converts angiotensin I into active octapeptide angiotensin II, and inactivates bradykinin via the kalikrein-kininogen system [12]. The ACE insertion/deletion (I/D) gene polymorphism (rs4340) is a 287 bp sequence of DNA in intron 16 of the ACE gene on chromosome 17q23, whereas there are a few polymorphisms that are in a linkage disequilibrium (rs 4341, rs4646994) in some populations [13]. In adults, plasma ACE does not change with age and it is only influenced by environmental or lifestyle factors to a minor extent [15-17]. Compared with rs4340 insertion/insertion (I/I) homozygotes, circulating ACE levels in plasma were found to be nearly 30.0 and 60.0% higher in I/D heterozygotes and deletion/deletion (D/D), homozygotes, respectively [14]. A meta-analysis of studies on glomerulosclerosis reported that the overall frequency of the D allele was 54.0% [13]. Overall frequency of the D allele was unrelated to gender but there were ethnic differences [13]. The ACE I/D gene polymorphism, which correlates with circulating ACE concentration, may be implicated in the etiology of DN, but it has been poorly investigated while giving inconsistent results [18-20]. The present study was undertaken to evaluate the association between rs4340 of the ACE gene and DN in Caucasian patients with T2DM.



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