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

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Author:
SUN Shu-zhen()
WANG Yi()
LI Qian()
TIAN Yong-jie()
LIU Ming-hua()
YU Yong-hui()
Journal Title:
CHINESE MEDICAL JOURNAL
Issue:
Volume 119, Issue 10, 2006
DOI:
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.

  • [1]Kreisberg JI,Ayo SH.The glomerular mesangium in diabetes mellitus.Kidney Int 1993; 43; 109.
  • [2]Gilbert RE,Cooper ME.The tubulointerstitium in progressive diabetic kidney disease:more than an aftermath of glomerular injury? Kidney Int 1999;56:1627-1637.
  • [3]Bruijn JA,Roos A,de Geus B,de Heer E.Transforming growth factor-beta and the glomerular extracellular matrix in renal pathology.J Lab Clin Med 1994;123:34-47.
  • [4]Eikmans M,Baelde J J,de Heer E,Bruijn JA.ECM homeostasis in renal diseases:A genomic approach.J Pathol 2003;200:526-536.
  • [5]McLennan SV,Fisher E J,Yue DK,Turtle JR.High glucose concentration causes a decreases in mesangium degradation.Diabetes 1994;43:1041-1045.
  • [6]McLennan SV,Yue DK,Turtle JR.Effect of glucose on matrix metalloproteinase activity in mesangial cells.Nephron 1998;79:293-298.
  • [7]Singh R,Song RH,Alavi N,Pegoraro AA,Singh AK,Leehey DJ.High glucose decreases matrix metalloproteinase-2 activity in rat mesangial cells via transforming growth factor-beta1.Exp Nephrol 2001 ;9:249-257.
  • [8]McLennan SV,Fisher E,Martell SY,Death AK,Williams PE,Lyons JG,et al.Effects of glucose on matrix metalloproteinase and plasmin activities in mesangial cells:possible role in diabetic nephropathy.Kidney Int Suppl 2000;77:S81-S87.
  • [9]Border WA,Noble NA.Evidence that TGF-beta should be a therapeutic target in diabetic nephropathy.Kidney Int 1998;54:1390-1391.
  • [10]Gilbert RE,CoxA,Wu LL,Allen TJ,Hulthen UL,Jerum S.Expression of transforming growth factor betal and type Ⅳ collagen in the renal tubuloin terstitium in experimental diabetes:effects of ACE inhibition.Diabetes 1998;47:414-422.
  • [11]Nakamura T,Takahashi T,Fukui M,Ebihara I,Osada S,Tomin O.Enalapril attenuates increased gene expression of extracellular matrix components in diabetic rats.J Am Soc Nephrol1995; 5:1492-1497.
  • [12]Mauer SM.Structural-functional correlations of diabetic nephropathy.Kidney Int 1994;45:612-622.
  • [13]Miner JH.Renal basement membrane components.Kidney Int 1999;56:2016-2024.
  • [14]Massova I,Kotra LP,Fridman R,Mobashery S.Matrix metalloproteinases:structures,evolution,and diversification.FASEB 1998;12:1075-1095.
  • [15]Suzuki D,Miyazaki M,Jinde K,Koji T,Yagame M,Endoh M,et al.In situ hybridization studies of matrix metalloproteinase-3,tissue inhibitor of metalloproteinase-1 and type Ⅳ collagen in diabetic nephropathy.Kidney Int 1997; 52:111-119.
  • [16]Mclennan SV,Martell SK,Yue DK.Effects of mesangium glycation on matrix metalloproteinase activities:possible role in diabetic nephropathy.Diabetes 2002;51:2612-2618.
  • [17]Mclennan SV,Kelly DJ,Cox AJ,Cao Z,Lyons JG,Yue DK,et al.Decreased matrix degradation in diabetic nephropathy:effects of ACE inhibition on the expression and activities of matrix metalloproteinases.Diabetologia 2002;45:268-275.
  • [18]Alderson NL,Chachich ME,Frizzel N,Canning P,Metz TO,Januszewski AS,et al.Effect of antioxidants and ACE inhibition on chemical modification of proteins and progression of nephropathy in the streptozotocin diabetic rat.Diabetologia 2004;47:1385-1395.
  • [19]Liu BC,Xu Y,Ma KL,Huang HQ,Yin LF,Liu DG.Effects of irbesartan on the expression of matrix metalloproteinase-2/tissue inhibitor of metallopro-teinase-2 in streptozotocin-induced diabetic rat kidney.Chin Med J 2005;118:1040-1044.
  • [20]Dong FQ,Li H,Cai WM,Tao J,Li Q,Ruan Y,et al.Effects of pioglitazone on expressions of matrix metalloproteinases 2 and 9 in kidneys of diabetic rats.Chin Med J 2004 ;117:1040-1044.
  • [21]Zaoui P,Cantin JF,Alimardani-Bessette M,Monier F,Halimi S,Morel F,et al.Role of metalloproteases and inhibitors in the occurrence and progression of diabetic renal lesions.Diabetes Metab 2000;26:S25-S29.
  • [22]Duan H J,Liu SX,Zhang YJ,Liu QJ,He N,Li YM.Effects of puerarin on renal function,expressions of MMP-2 and TIMP-2 in diabetic rats.Acta Pharmaceutica Sinica 2004 ;39:481-485.
  • [23]Leehey DJ,Singh AK,Alavi N,Singh R.Role of angiotensin Ⅱ in diabetic nephropathy.Kidney Int 2000;58:S93-S98.
  • [24]Tamura J,Konno A,Hashimoto Y,Kon Y.Upregulation of renal renin-angiotensin system in mouse diabetic nephropathy.Jpn J Vet Res 2005; 53:13-26.
  • [25]Jacobsen P,Rossing K,Parving HH.Single versus dual blockade of the renin-angiotensin system (angiotensin-converting enzyme inhibitors and/or angiotensin Ⅱ receptor blockers) in diabetic nephropathy.Curr Opin Nephrol Hupertns 2004; 13:319-324.
  • [26]Singh R,Alavi N,Singh AK,Leehey DJ.Role of angiotensin Ⅱ in glucose-induced inhibition of mesangial matrix degradation.Diabetes 1999; 48:2066-2073.
  • [27]Nankervis A,Nicholls K,Kilmartin G,Allen P,Ratnaike S,Martin FI.Effects of perindopril on renal histomorphometry in diabetic subjects with microal-buminuria:a 3-year placebocontrolled biopsy study.Metabolism 1998;47:12-15.
  • [28]Osterby R,Bangstad HJ,Rudberg S.Follow-up study of glomerular dimensions and cortical interstitium in microalbuminuric type 1 diabetic patients with or without antihypertensive treatment.Nephrol Dial Transplant 2000;15:1609-1616.
  • [29]Rudberg S,Osterby R,Bangstad H J,Dahlquist G,Persson B.Effect of angiotensin converting enzyme inhibitor or β-blocker on glomerular structural changes in young microalbuminuric patients with type 1 (insulindependent) diabetes mellitus.Diabetologia 1999;42:589-595.
  • [30]Deferrari G,Ravera M,Berruti V,Leoncini G,Deferrari L.Optimizing therapy in the diabetic patient with renal disease:antihypertensive treatment.J Am Soc Nephrol 2004;15:S6-S11.
  • [31]Noda M,Matsuo T,Nagano-Tsuge H,Ohta M,Sekiguchi M,Shibouta Y,et al.Involvement of angiotensin Ⅱ in progression of renal injury in rats with genetic non-insulindependent diabetes mellitus (Wistar fatty rats).Jpn J Pharmacol 2001; 85:416-422.
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