|Year : 2017 | Volume
| Issue : 4 | Page : 831-836
|Matrix metalloproteinase-9 and MMP-2 functional promoter polymorphisms and end-stage renal disease in dialysis patients: Correlation with oxidative stress marker
Hamid Nomani1, Hamed Abdi1, Asad Vaisi-Raygani2, Lida Hagh-Nazari1, Fariborz Bahremand2, Amir Kiani3, Zoherh Rahimi3, Ebrahim Shakiba1
1 Fertility and Infertile Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
2 Department of Pharmacology and Toxicology, Kermanshah University of Medical Sciences, Kermanshah, Iran
3 Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
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|Date of Web Publication||5-Oct-2017|
| Abstract|| |
Background: End-stage renal disease (ESRD) is a chronic clinical condition that starts with an initial damage and ultimately develops into a complete loss of kidney function with an unknown mechanism. MMP-9C1562T (rs243866) and MMP-2G1575A (rs3918242) polymorphisms in the promoter region are associated with the incidence of many diseases including cardiovascular, hypertension, chronic kidney disease (CKD), and diabetes mellitus which result in ESRD. Objective: This study was conducted to investigate the possible effect of MMP-9C1562T and MMP-2G1575A polymorphisms on the incidence of ESRD in Kermanshah population as well as their correlation with the serum level of malondialdehyde (MDA). Materials and Methods: The present study was conducted through a case-control method. A total of 136 unrelated ESRD patients and 137 unrelated healthy individuals as the control group matched with patients based on the age and sex. MMP-9C1562T and MMP-2G1575Apolymorphisms were determined using the PCR-RFLP method and serum levels of MDA by High performance liquid chromatography. Results: We found that the frequency of MMP-9C1562T and MMP-2G1575A functional promoter genotypes and alleles in ESRD patients was significantly different compared to the control group. MMP-9C1562T and MMP-2G1575A alleles act synergistically to increase the risk of ESRD by 1.41 times (P = 0.008). In addition, results of this study demonstrated that there is a significant increase in the serum level of MDA in the presence of a dominant model of MMP-9 genotypes (T/T+ C/T vs C/C) and MMP-2 genotypes (A/A+G/A vs G/G) in ESRD patients compared to controls also increased the risk of ESRD 1.36 and 1.4 folds, respectively. Conclusion: We found in this study that MMP-9C1562T and MMP-2G1575A alleles synergistically increase the risk of ESRD but also raise the serum level of MDA in ESRD patients. This information may be important in the evaluation of ESRD progression and in the elucidation of the mechanisms of the disease pathogenesis. Further studies with larger sample sizes and different ethnicities are necessary to confirm these findings.
Keywords: ESRD, matrix metalloprotein, oxidative stress marker, polymorphism
|How to cite this article:|
Nomani H, Abdi H, Vaisi-Raygani A, Hagh-Nazari L, Bahremand F, Kiani A, Rahimi Z, Shakiba E. Matrix metalloproteinase-9 and MMP-2 functional promoter polymorphisms and end-stage renal disease in dialysis patients: Correlation with oxidative stress marker. Ann Trop Med Public Health 2017;10:831-6
|How to cite this URL:|
Nomani H, Abdi H, Vaisi-Raygani A, Hagh-Nazari L, Bahremand F, Kiani A, Rahimi Z, Shakiba E. Matrix metalloproteinase-9 and MMP-2 functional promoter polymorphisms and end-stage renal disease in dialysis patients: Correlation with oxidative stress marker. Ann Trop Med Public Health [serial online] 2017 [cited 2019 Sep 17];10:831-6. Available from: http://www.atmph.org/text.asp?2017/10/4/831/215845
| Introduction|| |
End-stage renal disease (ESRD) refers to a disorder in which an individual suffers from a severe reduction in kidney function, associated with several disorders including atherosclerosis, arthritis, dyslipidemia, metabolic syndrome, and cardiovascular disease (CVD). Therefore, early detection of susceptibility of patients with ESRD to cardiovascular disease is of significant value. Evidences indicate that oxidative stress is one of the important factors involved in the development of CVD and atherosclerosis in patients undergoing maintenance hemodialysis.
It has been suggested that deficiency and alterations in the antioxidant mechanism and increased production of reactive oxygen species, oxidized LDL (ox-LDL), lipid oxidation index of malondialdehyde (MDA), and DNA damage are important factors in the initiation and progression of oxidative and atherogenic events.,
Several studies demonstrated that both increased free radicals production and down-regulated antioxidant enzymes activities contribute to protein, lipid, and DNA oxidative damage by-products accumulation in dialysis patients.,
In addition to the well-established fact that oxidative stress contributes to chronic inflammation of tissues and plays a central role in immunomodulation which may lead to renal failure, the role of genetic predisposition in enhanced oxidative damage has been noticed. In past years, the levels of some molecules involved in the mediation of inflammatory processes were reported to be increased in ESRD.,,, Among the effects of the inflammatory mediators, the induction of matrix metalloproteinase (MMPs a family of zinc-dependent enzymes) has been demonstrated. It has been recognized that MMPs play a significant role in the progression of atherosclerosis, plaque rupture, and ischemic heart disease.,
A growing number of reports suggest that MMP-2 and MMP-9 play some role in renal development, renal tubule physiology, glomerular pathophysiology, and ESRD. There are controversial data especially those obtained from studies on MMP-9-deficient mice, which shed new light on the functions of gelatinases in normal and diseased kidneys. Two types of gelatinases were produced by the 11-day kidney mesenchyme (11-day-old human mesenchyme tissue of kidney) which has been found to have a role in the early stages of kidney development., The role of MMP-2 (gelatinase A) in kidney is morphogenesis. Kidney morphogenesis will get damage by inhibiting the MMP-2 activity (gelatinase A) using specific antibodies or tissue inhibitor of MMPs (TIMPs).TIMP-2 has a overgrowth inhibition mechanism and branching of ureteric bud, embryonic collecting duct epithelial processing, and other process of nephron formation. However, the role of MMP-9 (gelatinase B or 92-kDa type IV collagenase) in kidney morphogenesis is still not clear.,,
This study was conducted to examine the possible effect of MMP-2(-1575 G/A) and MMP-9 (-1562C/T) polymorphisms on the incidence of ESRD in Kermanshah population and also its association with a serum level of malondialdehyde. However, the clinical significance of MMP-2(-1575 G/A) and MMP-9 (-1562C/T) functional promoter genotypes allele in ESRD is not clear. Here, we studied the possible effect of MMP-2-G1575A and MMP-9-C1562T functional promoter polymorphisms in the development of ESRD and their association with the lipid peroxidation marker (MDA) in Iranian patients with ESRD.
| Materials and Methods|| |
In this case-control study, 272 subjects including 136 hemodialysis patients with ESRD (MHD; mean age 58.1 ± 13.3 years; 89 male and 47 female) that were going under the dialysis for at least three times a week. They were selected from the Nephrology Unit of Imam Reza hospital of the Kermanshah University of Medical Sciences. The control group consisted of 137 individuals (mean age 55.7 ± 7.3 years; 87 male and 50 female) without any obvious renal complications as determined by the level of urea and creatinine in their serum. Controls and patients were sex and age matched. The study protocol was approved by the Ethics Committee of the Kermanshah University of Medical Sciences and was in accordance with the principles of the Declaration of Helsinki II. All subjects provided written informed consent.
A total of 5 mL of venous blood sample were collected from patients (pre-dialysis) and control subjects where 3 mL of the blood samples were collected in EDTA vials for genomic DNA extraction and 2 mL blood without EDTA was used for biochemical analysis.
Genomic DNA was extracted from peripheral blood leukocytes using the phenol-chloroform extraction method. The purity and concentration of extracted DNA was measured by the Nanodropspectrophotometer (Thermo 2000C model).
Genotyping of all individuals was done without knowledge of their groups or disease. Genotyping of the single-nucleotide polymorphism of the MMP-9C1562T (rs243866) functional promoter was performed by the polymerase chain reaction (PCR) (MMP-9: forward primer 5-GCC TGG CAC ATAGTA GGC CC-3 and reverse primer 5-CTT CCTAGC CAG CCG GCA TC-3 primer). The MMP-9-C1562T allele was detected by treating their corresponding PCR products with SphI (5 U, Fermentas) restriction end nuclease at 370C. The PCR product corresponding to MMP-9-1562C (435 bp) allele was not cleaved by SphI, whereas the PCR products containing the MMP-9-C1562T allele was cleaved by the SphI enzyme, generating 244 and 191 bp DNA fragments and heterozygotes of _1562C and T alleles were cleaved by the enzyme producing 435, 244, and 191 bp fragments.,
The MMP-2 nucleotide polymorphism at position 1575 was determined by PCR using 5′-CACACCCACCAGACAAGCCT-3′ and 5′-TGGGGAATATGGGGAATGTT-3′ as the forward and reverse primers, respectively. The PCR amplification reaction contained 50-100 nggenomic DNA, 10 pmol of each primer, 200 mM of each dNTP, and 0.5 U Taq DNA polymerase in the Taq DNA reaction buffer. After the DNA was denatured at 95°C for 5 minutes, the reaction mixture was subjected to 35 cycles of 94°C for 1.0 minute, 58.2°C for 1.0 minute, and 72°C for 1.5 minutes with a final extension time of 10 minutes. PCR products were digested with RcaI (PagI) restriction endonuclease at 37°C for 5 hours and the digested products were separated on a 2.5% agarose gel and visualized by ethidium bromide staining. The PCR product of MMP-2 1575G (349 bp) allele is not cleaved by RcaI, whereas that of the MMP-2 1575A allele is cleaved by the enzyme generating 260 and 89 bp fragments and heterozygotes of _1575G and A alleles are cleaved by the enzyme producing 349, 260, and 89 bp fragments.
Measurement of plasma levels of malondialdehyde
Serum MDA concentration was measured by HPLC (Agilent Corp. Germany) using the EC 250/4.6 Nucleodur 100-5 C18ec column (Macherey-Nagel, Duren, Germany) as we described previously.,
The allelic frequencies were calculated by the gene counting method. The MMP-9C1562T (rs243866) and MMP-2G1575A (rs3918242) functional promoter genotypes and allele frequencies in ESRD patients were compared to controls using the t2 test. Odds ratios (OR) were calculated as estimates of relative risk for disease and 95% confidence intervals (CI) obtained by SPSS logistic regression. The interaction between MMP-9C1562T (rs243866) and MMP-2G1575A (rs3918242) functional promoter polymorphisms was determined using a logistic regression model. The correlation of serum level of MDA with the MMP-9C1562T (rs243866) and MMP-2G1575A (rs3918242) functional promoter polymorphisms between studied groups was calculated using linear regression and unpaired t test (Pearson and Spearman). A two-tailed Student's t test, analysis of variance (ANOVA), and nonparametric independent-sample Mann-Whitney analyses were used to compare quantitative data. Statistical significance was assumed at P < 0.05. The SPSS statistical software (SPSS for Windows 16; SPSS Inc. Chicago, IL, USA) was used for the statistical analysis.
| Results|| |
Characteristics of ESRD patients and control subjects are shown in [Table 1]. There was no significant difference between the mean of age and sex of the two groups. The patients with ESRD had significantly higher plasma MDA concentration (2.04 ± 0.4 vs 1.1 ± 0.33 μM, P < 0.001) compared to control subjects.
|Table 1: Characteristics and distribution of risk factors in patients with end stage renal disease (ESRD) and control subjects in a population from western Iran|
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MMP-9 and MMP-2 genotypes and alleles
Odds ratio and the frequency of MMP-9C1562T(rs243866) and MMP-2G1575A (rs3918242) functional promoter genotypes and alleles in ESRD patients and the control group are shown in [Table 2] and [Table 3]. As shown in [Table 2] and [Table 3], the overall distribution of the MMP-9C1562T(rs243866) and MMP-2G1575A(rs3918242) genotypes and alleles in ESRD patients were significantly different from that of the control group (χ2=8.4, df=2, P = 0.042) and (χ2=7.3, df(degrees of freedom) = 2, P = 0.026) for alleles (χ2=7.6, df=1, P = 0.006) and (χ2=6.9, df=1, P = 0.009), respectively.
|Table 2: Odd ratio and distribution of MMP-9 genotypes and alleles with respect to C/C or C respectively in ESRD patients after adjusted sex and age|
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|Table 3: Odd ratio and distribution of MMP-2 genotypes and alleles with respect to C/C or C respectively in ESRD patients after adjusted sex and age.|
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The age- and sex-adjusted OR indicated that both dominant (C/T+T/T vs C/C) and allele T of MMP-9C1562T (rs243866) functional promoter gene polymorphism significantly increased the risk of SLE by 1.36 (1.06-1.8, P = 0.016) and 1.32 (1.07-1.6, P = 0.009) times, respectively. In addition, both dominant (G/A+A/A vs G/G) and allele A of MMP-2C1562T (rs243866) functional promoter gene polymorphism CTLA-4 G-1661A codominant (G/A vs GG) gene polymorphism significantly increased the risk of SLE by 1.4 (1.1-1.8, P = 0.008) and 1.34 (1.1-1.7, P = 0.005 times), respectively.
We analyzed the relation of dominant models (C/T+T/T vs C/C) of MMP-9C1562T (rs243866) and (G/A+A/A vs G/G) MMP-2G1575A (rs3918242) functional promoter genotypes with a serum level of MDA. As shown in [Table 4], ESRD patients with one or two copies of T allele (C/T+T/T) of MMP-9C1562T and one or two copies of A allele of MMP-2G1575A had significantly higher MDA (P< 0.001) compared with ESRD and control subjects with the same allele. Although in both dominant models of MMP-9C1562T C/T+T/T compared with C/C and MMP-2G1575A G/A+A/A with G/G had a higher serum level of MDA, but these differences were not significant.
|Table 4: Comparison of MDA concentration level between dominant model of MMP-9 genotypes (T/T + C/T vs. C/C) and MMP-2 genotypes (A/A + G/A vs. G/G) in ESRD subjects and control group|
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To investigate the interaction between MMP-9C1562T T and MMP-2-G1575A alleles in ESRD patients, logistic regression analysis was used and results are presented in [Table 5]. We found that there is a strong and significant interaction between MMP-9-C1562T and MMP-2-G1575A alleles (χ2=7.2, df=1, P = 0.007). This interaction increased the risk of ESRD by 1.41 times (1.08-1.66, P = 0.008).
|Table 5: Carrier odds ratios interaction between MMP-2 A allele and MMP-9 T allele in ESRD patients compared with control group|
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| Discussion|| |
ESRD and chronic kidney disease (CKD) are multifactor chronic diseases that are caused by complex interactions between genetic, environmental, and hormonal factors.,,, CKD and ESRD are increasingly recognized as a major public health problem in the world. ESRD is a progressive and irreversible deterioration in renal function associated with high levels of free radicals. Two possible causes of progression of ESRD disease are inflammation and oxidative stress.,,
In addition, MMP-9 and MMP-2 have been shown to be involved in inflammation, oxidative stress and may increase the risk and the development of CVD, hypertension, and preeclampsia.,, Furthermore, a growing number of reports suggest that MMP-2 and MMP-9 play some role in renal development, renal tubule physiology, and glomerular pathophysiology; therefore, these two enzymes may have an effect on the pathogenesis of ESRD and CKD., This case-control study for the first time demonstrated that both functional promoter polymorphism of MMP-2-G1575A and MMP-9-C1562T alleles act in synergy to increase the risk of ESRD. We found that the MMP-9 C1562T and MMP-2 G1575A alleles independently increased the risk of ESRD 1.32 and 1.34-fold, respectively. The concomitant presence of both MMP-9T and MMP-2A alleles in individuals increased their susceptibility to ESRD 1.41-fold. Results of this study also demonstrated that the serum level of MDA is significantly elevated in ESD patients compared with controls. The serum level of MDA (P < 0.001) in ESRD patients with dominant models of MMP-9 C1562T (C/T+T/T) and MMP-2 G1575A (G/A+A/A) was significantly higher than that in the control group. These observations emphasize that the significance of dominant models of MMP-9 C1562T (C/T+T/T) and MMP-2 G1575A (G/A+A/A) affects the inflammation process and lipid peroxidation in the development of ESRD. These results support the hypothesis that MMP-9 C1562T and MMP-2 G1575A alleles are associated with the increased risk of ESRD development.,
Genetic polymorphisms in MMP-9 C1562T and MMP-2 G1575A genes affect MMP-9 and MMP-2 levels.,, These genotypes have been reported to decrease the MMP-9 expression although there was an increase in the MMP-2 expression, thereby supporting the hypothesis that MMP-9 T allele and MMP-2 A alleles have an increased role in the progression of kidney diseases. This is in consistent with the study that reported that MMP-2 genotypes or haplotypes modify MMP-2 levels (increased level) in ESRD patients and may help to identify patients with the increased MMP-2 activity in plasma., Hirakawa et al. demonstrated that the genetic of MMP-9 was associated with ESRD. One report showed that MMP-9 has a significant role in the progression CDK: a new biomarker of resistant albuminuria.
Other study reported that circulating MMP levels MMP-2, -3, and -9 are independently associated with kidney disease progression in non-diabetic CAD patients and add incremental predictive power to conventional risk factors. This is consistent with the study performed by Hecht et al. which showed that MMP-2 and MMP-9 could have a contributive role in uremic vascular calcification in vivo and in vitro. They suggested that the inhibition of MMP-2 and MMP-9 seems a promising strategy in the prevention of vascular calcifications.
We previously reported that MMP-9-C1562 T and MMP-2-G1575A alleles synergistically increase the risk of SLE but also high serum levels of MDA, neopterin, and circulatory levels of MMP-2 and lower MMP-9 in SLE patients., In consistent with our result, Okada et al. reported that the potentially functional polymorphisms of MMP-9 were associated with the prevalence of CKD in a large Japanese population. Rahimi et al. indicated a significant relationship between the MDA serum level and diastolic blood pressure in 168 preeclamptic patients and 154 controls. Ozbasar et al. pointed to the therapeutic use of NO and MDA reduction in patients with chronic kidney failure.
| Conclusion|| |
We reported, for the first time, that the concomitant presence of both MMP-2 1575A and MMP-9 1562T alleles synergistically increased the risk of SLE 1.41-fold. In addition, we found that carriers of the MMP-9 T and MMP-2 A alleles have a distinct high serum level of MDA. This information may be important in the evaluation of ESRD progression and in the elucidation of the mechanisms of the disease pathogenesis. However, due to the heterogeneous picture of ESRD and the influence of a subset of risk factors in the development of the disease, further studies with larger sample sizes and different ethnicities are necessary to verify our findings.
This work was performed in partial fulfillment of requirements for an M. Sc degree in Clinical Biochemistry, Kermanshah University of Medical Sciences, Kermanshah, Iran (HamedAbdi). All authors contributed equally to this study.
Financial support and sponsorship
The Kermanshah University of Medical Sciences, Kermanshah, Iran (grant number 91064).
Conflict of interest
There are no conflicts of interest.
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Department of Clinical Biochemistry, Kermanshah University of Medical Sciences, Kermanshah
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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