Diabetic nephropathy (DN) is a progressive disease elicited by chronic exposure to hyperglycemia and is a leading cause of ESRD. Dia-betic nephropathy is a chronic complication of both type 1 DM (beta cell destruction –absolute lack of insulin) and type 2 DM (insulin resistance and/or decreased secretion of insulin) (Bennett and Aditya, 2015).
Nitric oxide (NO), is synthesized from L-arginine by the enzyme endothelial nitric oxide synthase (eNOS) (NOS3) (Mohsen et al., 2006). It regulates endothelial function and precipitates vasodilatory effects in multiple organs, including the kidney. (Noiri et al., 2002).
Endothelial dysfunction is a major cause of pathogenesis of diabet-ic vascular disease, including diabetic nephropathy(DNP). A single nu-cleotide polymorphism in (eNOS) gene affects the activity of eNOS and is associated with endothelial dysfunction (Samant and Sandepa ., 2016).
Several polymorphisms of the eNOS gene have been identified, and their association with various diseases has been investigated (Zintza-ras, et al., 2009). This study was aimed to find out the possible associa-tion and synergistic effect between eNOS 4a/b and G894T Polymor-phisms on the risk of diabetic nephropathy in Type 2 Diabetes mellitus.
This study was conducted at the internal medicine and clinical pa-thology departments of Benha University Hospitals from April 2015 to July 2016 on 45 patients with diabetes mellitus type 2 and 15 apparently healthy subjects serving as a control group. Patients were further classi-fied according to their albumin / creatinine ratio (ACR) into three groups- (15) normoalbuminuric diabetic group, (15) microalbuminuric diabetic
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group and (15) diabetics with macroalbuminuria. All patientsʼ age at di-agnosis of diabetes was ≥30 years and the duration of diabetes was ≥5 years, while type 1 diabetes mellitus, type 2 diabetes mellitus patients of less than 5 years’ duration and other causes of nephropathy were exclued.
All patients were subjected to full history taking and clinical exam-ination. Blood samples were drawn from all to assess levels of FBG, HbA1c, total cholesterol, TG, HDL-C, LDL-C, creatinine. All candidates were genotyped for the ENOS polymorphism using PCR-RFLP tech-nique.
The results of this work are summarized as the following:
❖ There was no statistically significant difference between the studied groups regarding sex and age.
❖ As regarding the serum creatinine, there was a significant increase of serum creatinine in diabetic patients with macroalbuminuria com-pared to the microalbuminuric and normalbuminuric diabetic group.
❖ As regarding the lipid profile, the patient group showed higher levels of total cholesterol, TG and LDL-C than control group (p=0.001). While, no statistically significant difference between the studied groups regarding HDL-C (P>0.05). Also, a significant increase as regard total cholesterol, TG and LDL-C in macroalbuminuric diabet-ic group compared to microalbminuric and normoalbuminuric groups. HDL-C was significantly lower in macroalbuminric group compared to microalbuminuric and normoalbuminuric patients (p˂0.05).
❖ The fasting blood sugar was higher in patients with advanced stage of diabetic nephropathy (macroalbuminuric diabetic patients) com-
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pared to normoalbuminuric diabetic patients and microalbuminuric diabetic patients but not reach a significant level.
❖ A significant increase in HbA1c in patient group compared with control group, and in macroalbuminuric diabetic group compared to microalbuminuric group. Also, it showed significant difference be-tween microalbuminuric and normoalbuminuric diabetic groups (p=0.001).
❖ Regarding urinary ACR, there was a statistically higher significant difference between patient group compared to control group (p T SNP, the GT genotype was significantly more fre-quent in diabetics with DN (micro and macroalbuminuria) 17
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(56.7%) than in normoalbuminuric diabetics 1 (6.7%), p = 0.001 and associated with risk of developing DN by 18.3folds. Also, subjects with GT genotype were 3.14folds risky to develop microalbuminuria and 3.5 folds risky to develop macroalbuminuria than control group. Similarly, the T allele was more frequent in the DN group 17(28.3%)than in diabetics without nephropathy1(3.3%), (p =0.005).
❖ There were significant differences in genotype and allele frequencies between patients and control for eNOS (4a/b) polymorphism (patient group aa genotype was 24(53.3%) while control group was 2(13.3%), p value 0.007.
❖ There was no significant difference in the distribution of eNOS 4a/b genotypes between the three diabetic groups. The frequency of eNOS aa genotype was 53.3% in macroalbuminuric patients,73.3% in microalbuminuric and 33.3% in normoalbuminuric ones p˃0.05.
❖ There was statistically significant difference in frequency of aa gen-otype in microalbuminuria group compared with control group and in macroalbuminuria group compared with control group(P7%, Creatinine and HDL-c as independent factors. The genotype (GT), allele T, HbA1c, serum Creatinine were found to be independent predictors for DN (p˂0.05).
In conclusion, this study suggests that the presence of either eNOS 4a/b or G894T polymorphisms increases the risk of diabetic nephropathy but they have no synergistic effect, and their detection can be used as a novel method to detect susceptibility to DN in Egyptians with type 2 diabetes. |
