Effects Of Rosiglitazone On Serum Matrix Metalloproteinase 2 In Patients With Early Type 2 Diabetic Nephropathy

Object:Type 2 diabetes mellitus is a common endocrine disease and diabetic nephropathy (DN) is one of the main chronic complication, but also one of the leading causes of death. At present, the diabetes patients constently increase, type 2 diabetes accounting 93%, about 40% with diabetic nephropathy. According statistic of autopsy in developed country, the incidence of DN ranges from 10% to 75%,50% patientes of DM suffer the DN when the DM history is over ten years. An annual increase in end-stage renal disease, diabetes led to the proportion increased year by year. The basic pathological changes of diabetic nephropathy is the glomerular basement membrane thickening and extracellular matrix increasing, lead to accumulation of extracellular matrix(ECM). Alteration of matrix metalloproteinases and tissue inhibitor expression and activity correlated with accumulation of extracellular matrix. At home and abroad has been reported in the literature, serum matrix metalloproteinase-2 expression was significantly decreased in patients with diabetic nephropathy, and become obviously with the course of disease. Therefore, this subject study the effects of rosiglitazone on serum matrix metalloproteinase-2 in patients with early diabetic nephropathy, and explore the possible mechanism of rosiglitazone's treatment to diabetic nephropathy.Material and Methods: The 80 cases of type 2 diabetic nephropathy come from the second hospital of jilin university endocrinology department from July 2006 to October 2007, without all kinds of acute and chronic infectious diseases, diabetic ketoacidosis, non-diabetic nephropathy disorders, liver disorders , Graves disease, pulmonary fibrosis and collagen diseases and tumors so on. Urinary albumin excretion rate (UAER) average from 20 to 200 ug / min, and receive adjustment lipids, reduce urinary protein and insulin treatment. The patientes are randomly divided into rosiglitazone group(A) and control group (B) treat for 12 weeks. The patients of group A receive 8mg rosiglitazone on the basis of primary treatment in daily morning (rosiglitazone maleate by Glaxo Smith Kline company), the original treatment plan of Group B unchanged. In group A, there are 40 cases, including 24 male cases, 16 female cases. The average age is (43.35±9.82) years, course of disease ranges from 4 to 12. In Group B, there are 40 cases, including 22 male cases, 18 female cases, the average age is (43.17±10.43)years, course of disease ranges from 4 to 12. There is equilibrium between the two groups according materials.Before and after 12 weeks treatment, intravenous fasting blood glucose(FBG),triglycerides(TG), total cholesterol(TC), low-density lipoprotein cholesterol(LDL-C) and high-density lipoprotein cholesterol(HDL-C) determined by the automatic biochemistry machine; glycosylated hemoglobin(HbA1c) is determined by Bio-Rad D-10 hemoglobin A1c detector ion exchange HPLC; urinary albumin is determined by radioimmunoassay, and calculate urinary albumin excretion rate(UAER) ; serum matrix metalloproteinase-2(MMP-2) is determined by zymography detection.Measurement data is manifested by x±?s and analyzing t-test, test of homogeneity variance, and multiple linear regression analysis by the SPSS10.0 software.Conclusion:1.After treatment, the control group's FBG decreased(P<0.05), and TG,TC,LDL-C,UAER significantly decreased compare with before treatment(P<0.01).Levels of HbA1c decreased, but not statistically significant(P>0.05). Levels of HDL-C and MMP-2 were significantly higher compared with before treatment(P<0.01). 2.After treatment, the rosiglitazone group's FBG, HbA1c, TG, TC, LDL-C, UAER significantly decreased comparing with before treatment(P<0.01). Levels of HDL-C and MMP-2 were significantly higher compared with before treatment(P<0.01). 3.After rosiglitazone treatment FBG, UAER decrease more significantly compared with the control group(P<0.01), MMP-2 also increase more significantly(P<0.01). 4.The alteration of MMP2 does not correlated with the change of FBG, HbAlc, TG, LDL-C, HDL-C and UAER.Discussion: Glomerular basement membrane thickening and the extracellular matrix are the main reason leading to renal dysfunction of DN. Lost of balance between the ECM composition and degredation play an important role in this procedure. At past ,the most research focus on the increasing of ECM composition while the decreasing of ECM has being paid attention by the researcher. And matrix degradation of the enzyme include matrix metalloproteinases (MMPs), plasminogen (plasmin), the cysteine protease, caspase-four, in while MMPs plays the important role.MMPs is a kind of neutral endonuclease compositing zincum which is composited and secreted by the connective tissue cells, endothelial cells, monocyte, macrophages, neutrophils, inherent glomerular cells, renal tubular epithelial cells, the tumor cells so on. The molecular structure is made up of four kinds of structure domain which include N-terminal signal peptide, enzyme peptide (associated with enzyme activity), the catalytic region (binding sites), the combination of C-terminal region (with a specific matrix, or the cell surface receptor binding).At present, MMPs have nearly 23 members of the family, according to the different substrate is broadly divided into:①interstitial collagenase;②Ⅳof collagenase / gelatin enzymes (MMP-2, MMP-9);③plastic matrix enzyme dissolved enzyme;④membrane matrix metalloproteinases. The main ingredients of ECM and glomerular basement membrane are collagenⅣ(C-Ⅳ), and degradated mainly by matrix metalloproteinase-2 (MMP-2). Present research indicates that, the activity of MMPs decrease whether human being, mouse or rat mesangial cells are cultured in high glucose secretion. Possible reasons for MMPs decreasing include:①Hyperglycemia mediate and generate some certain kinds of cytokines, such as transforming growth factor TGFβ1, not only a variety of ECM components directly stimulate the formation of MMPs also inhibit the biosynthesis process, inhibit the activity of MMPs.②The alteration of kidney composition of the organizational structure in DM, resulting in increasedα2-macroglobulin globulin,α2-MG is a nonspecific protease inhibitor, can be formedα2-macroglobulin globulin-protease complex, inhibited the activity of MMPs.③Hyperglycemia inhibit the activity of MMPs by plasminogen activator inhibitor-1 (PA-1), plasminogen is another ECM-degrading enzyme systems, and can activate MMPs, high sugar can competitive cell surface and the surrounding plasminogen, and stimulate cell surface expression of PAI-1, thereby inhibiting the activity of MMPs.④Hyperglycemia can activate the triglyceride (DAG) - protein kinase C (PKC) pathway, many high blood sugar can promote DAG metabolite synthesis, and further activate PKC, PKC has not only promoted the transcription of TGFβ1, and inhibited defibrillators Plasminogen activator (PA), which through various channels inhibit the activity of MMPs.⑤Hyperglycemia mediate and generate a variety of cytokine can also be induced TIMPs, Some researcher find that TGFβcan increase TIMPs -1 expression in the vitro culturing mononuclear cell, TIMPs are specific inhibitors of MMPs, and can block MMPs substrate, thereby inhibit MMPs to reduce the degradation of ECM. Decreasing of expression and activity of MMPs lead to accumulation of ECM, Correcting the MMPs expression and activity abnormality play a important role in reducing ECM accumulation and delaying glomerular sclerosis.Thiazolidinediones drugs such as rosiglitazone for clinical insulin-sensitizing agents can reduce the target tissue to insulin resistance and increase the liver, fat and muscle of blood circulation in insulin sensitivity. Research shows that they can reduce insulin secretion, and effective control of blood sugar, can help in treatment of pancreaticβ-cell rest, thereby reducing isletβ-cell function failure and the risk of hypoglycemia. In recent years, many scholars at home and abroad in vitro experiments, animal tests and clinical studies have found Thiazolidinediones drug on diabetic nephropathy have some protection, but protection mechanisms have not yet entirely clear. The results show that rosiglitazone combined with the use of insulin therapy in type 2 diabetic nephropathy after 12 weeks, not only blood glucose, blood lipids, urinary albumin excretion rate had improved, but also improved the expression of serum matrix metalloproteinase-2. Correlation analysis shows improvement of MMP2 expression don't have relationship with improvement of blood glucose, blood lipids, urinary albumin excretion rate, therefore, to speculate rosiglitazone may have directly increased expression of serum matrix metalloproteinase-2. Thereby increasing the degradation of the ECM to reduce the accumulation of ECM, retard the occurrence of diabetic nephropathy and development. The mechanism may be Thiazolidinediones drugs and the combination of PPARγinhibited expression of plasminogen activator inhibitor 1 (PAI-1),PAI-1 on the reduction of plasminogen, and the activity of MMP-2 inhibition, thereby increasing the expression of MMP-2.Conclusion:Thiazolidinediones drug such as rosiglitazone can improve type 2 diabetic nephropathy patients in blood glucose, blood lipids and reduce urinary albumin excretion rate, directly raise expression of serum matrix metalloproteinase-2, thus increasing the extracellular matrix degradation, delay the occurrence and development of diabetic nephropathy. And Thiazolidinediones drugs in kidney protection mechanisms has opened up a new line of thought.