Effects of benazepril on renal function and kidney expression of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 in diabetic rats.
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 undertaken 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 establishment of DM model, benazepril (10 mg.kg(-1).d(-1)) was given to the DL group for 12 weeks, and the same 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.
Sun
Shu-zhen
SZ
Department of Pediatrics, Shandong Provincial Hospital, Shandong University, Jinan 250021, China.
Wang
Yi
Y
Li
Qian
Q
Tian
Yong-jie
YJ
Liu
Ming-hua
MH
Yu
Yong-hui
YH
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D024141:Collagen Type IV / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007678:Kidney Glomerulus / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000032:analysis* / Q000235:genetics; D009929:Organ Size; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000032:analysis* / Q000235:genetics
D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D001786:Blood Glucose; D024141:Collagen Type IV; D019716:Tissue Inhibitor of Metalloproteinase-2; D013311:Streptozocin; D020778:Matrix Metalloproteinase 2; C044946:benazepril