Paper - WANFANG MED ONLINE

You Position: Home > Paper

Effects of benazepril on renal function and kidney expression of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 in diabetic rats

( views:145, downloads:0 )

Author:: No author available

Journal Title:: CHINESE MEDICAL JOURNAL

Issue:: 10

DOI:: No doi available

Key Word:: angiotensin converting enzyme inhibitors;diabetic nephropathy;renal function;matrix metalloproteinase-2;tissue inhibitor of metalloproteinase-2

Abstract： Background Excessive deposition of extracellular matrix (ECM) in the kidney is the hallmark of diabetic nephropathy. Increased matrix synthesis has been well documented but the effects of diabetes on degradative pathways, particularly in the in vivo setting. The renal protective effect of these pathways on matrix accumulation has not been fully elucidated. The present study was understaken to investigate the activity of matrix metalloproteinase-2 (MMP-2), the expression of MMP-2 and tissue inhibitor of metalloproteinase-2 (TIMP-2) in kidney tissues of diabetic rats, and to explore the degradative pathway of type Ⅳ collagen (Ⅳ-C) and the renal protective effects of ACE inhibition-benazepril.Methods Twenty-four healthy male Wistar rats were divided randomly into normal control group (NC group),untreated diabetes mellitus group (DM group), and diabetes mellitus group treated with benazepril (DL group).The rat model of diabetes mellitus was induced by intraperitoneal injection of streptozocin (60 mg/kg). After the volume of water was given to the other two groups. At the end of 12 weeks, renal function was evaluated with 24-hour urinary protein (Upro), clearance of creatinine (Ccr), and blood urea nitrogen (BUN). MMP-2 activity was determined by gelatin zymography. The levels of MMP-2,TIMP-2 and collagen Ⅳ (Ⅳ-C) protein in the kidney tissue were assessed by immunohistochemistry. The gene expression of MMP-2 and TIMP-2 was measured by reverse transcription polymerase chain reaction (RT-PCR).Results The levels of BUN, Upro and Ccr in the DM group were higher than those in the NC group. In the DM group, the mRNA, enzymatic activity and proteins of MMP-2 decreased, but the expressions of Ⅳ-C and TIMP-2 increased. All diabetes-associated changes in renal function and MMP/TIMP were attenuated after benazepril treatment with reduced Ⅳ-C accumulation.Conclusions The changes of MMP-2 and TIMP-2 expressions in kidney tissues of diabetes rats may contribute to the occurrence and progression of diabetic nephropathy. Benazepril could exert protective effects on diabetic nephropathy, owing to the upregulation of MMP-2 and downregulation of TIMP-2 expressions, which further inhibits the excessive deposition of extracellular matrix in the glomerulus.

Reference

[1]段惠军,刘淑霞,张玉军,等.葛根素对糖尿病大鼠肾功能及肾组织MMP-2与TIMP-2表达的影响[J].2004,(7).
[2]董凤芹,李红,蔡卫民,等.Effects of pioglitazone on expressions of matrix metalloproteinases 2 and 9 in kidneys of diabetic rats[J].2004,(7).
[3]LIU Bi-cheng,XU Yan,MA Kun-ling,etc.Effects of irbesartan on the expression of matrix metalloproteinase-2/tissue inhibitor of metalloproteinase-2 in streptozotocin-induced diabetic rat kidney[J].2005,(12).
[4]J I, Kreisberg,S H, Ayo.The glomerular mesangium in diabetes mellitus.[J].1993,43(1).
[5]Eikmans M,Baelde JJ,de Heer E,etc.ECM homeostasis in renal diseases: a genomic approach.[J].2003,200(4).
[6]T, Nakamura,T, Takahashi,M, Fukui,etc.Enalapril attenuates increased gene expression of extracellular matrix components in diabetic rats.[J].1995,5.
[7]Yue DK,Turtle JR,McLennan SV.Effect of glucose on matrix metalloproteinase activity in mesangial cells.[J].1998,79(3).
[8]I, Massova,L P, Kotra,R, Fridman,etc.Matrix metalloproteinases: structures, evolution, and diversification.[J].1998,12(12).
[9]Kon Y,Tamura J,Konno A,etc.Upregulation of renal renin-angiotensin system in mouse diabetic nephropathy[J].2005,53(1).
[10]A, Nankervis,K, Nicholls,G, Kilmartin,etc.Effects of perindopril on renal histomorphometry in diabetic subjects with microalbuminuria: a 3-year placebo-controlled biopsy study.[J].1998,47.
[11]R, Osterby,H J, Bangstad,S, Rudberg.Follow-up study of glomerular dimensions and cortical interstitium in microalbuminuric type 1 diabetic patients with or without antihypertensive treatment.[J].2000,15.
[12]ustin.unimelb.edu.au,Hulthen UL,Allen TJ,etc.Expression of transforming growth factor-beta1 and type IV collagen in the renal tubulointerstitium in experimental diabetes: effects of ACE inhibition.[J].1998,47(3).
[13]S M, Mauer.Structural-functional correlations of diabetic nephropathy.[J].1994,45.
[14]Ravera M,Deferrari G,Leoncini G,etc.Optimizing therapy in the diabetic patient with renal disease: antihypertensive treatment.[J].2004,15(Suppl.1).
[15]Miyazaki M,Yagame M,Sakai H,etc.In situ hybridization studies of matrix metalloproteinase-3, tissue inhibitor of metalloproteinase-1 and type IV collagen in diabetic nephropathy.[J].1997,52(1).
[16]W A, Border,N A, Noble.Evidence that TGF-beta should be a therapeutic target in diabetic nephropathy.[J].1998,54.
[17]Martell SK,Yue DK,McLennan SV.Effects of mesangium glycation on matrix metalloproteinase activities: possible role in diabetic nephropathy.[J].2002,51(8).
[18]S. Rudberg,R. Østerby,H.-J. Bangstad,etc.Effect of angiotensin converting enzyme inhibitor or beta blocker on glomerular structural changes in young microalbuminuric patients with Type I (insulin-dependent) diabetes mellitus[J].1999,42(5).
[19]Miner JH.Renal basement membrane components.[J].1999,56(6).
[20]Song RH,Alavi N,Singh AK,etc.High glucose decreases matrix metalloproteinase-2 activity in rat mesangial cells via transforming growth factor-beta1.[J].2001,9(4).
[21]Leehey DJ,Singh AK,Alavi N,etc.Role of angiotensin II in glucose-induced inhibition of mesangial matrix degradation.[J].1999,48(10).
[22]J A, Bruijn,A, Roos,B, de Geus,etc.Transforming growth factor-beta and the glomerular extracellular matrix in renal pathology.[J].1994,123.
[23]Rossing K,Parving HH,Jacobsen P.Single versus dual blockade of the renin-angiotensin system (angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers) in diabetic nephropathy.[J].2004,13(3).