NDT Advance Access originally published online on October 31, 2007
Nephrology Dialysis Transplantation 2008 23(3):896-903; doi:10.1093/ndt/gfm710
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Upregulation of tissue inhibitor of metalloproteases-1 (TIMP-1) and procollagen-N-peptidase in hypertension-induced renal damage
1 Renal Research Group, Department of Medicine, Haukeland University Hospital, Bergen, Norway 2 Institute of Medicine, University of Bergen, Bergen, Norway 3 Department of Pathology, Haukeland University Hospital, Bergen, Norway
Michael Hultström, Renal Research Group Institute of Medicine, University of Bergen, N-5021 Bergen, Norway. Tel: +4755972959, Fax: +4755975890, E-mail: Michael.Hultstrom{at}med.uib.se
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Abstract |
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Background. Hypertensive renal damage starts in the juxtamedullary cortex (JMC) and gradually extends towards the outer cortex (OC). The intention of the study was to examine if the increase of fibrous tissue in the JMC of the spontaneously hypertensive rat (SHR) is dependent on an increase of collagen synthesis or a decreased collagen breakdown compared to the normotensive control (WKY).
Methods and results. The renal damage was evaluated by light microscopy, and the amount of fibrosis was quantified using Sirius red staining. Real-time RT-PCR was used to quantify mRNA for: collagen-type-1-alpha-1 (col1a1), procollagen-n- and -c-proteinase, matrix metalloproteases, MMP-2 and MMP-9, tissue inhibitor of metalloproteases, TIMP-1 and TIMP-2. Western blot was used to quantify the proteins of MMP-2, MMP-9, TIMP-1 and TIMP-2. The relative activities of MMP-2 and MMP-9 were assayed by zymography. The JMC in SHR had an increased amount of collagen as measured by Sirius red, and a 15-fold increase in the mRNA for col1a1. The gene expression of procollagen-c-proteinase was unchanged while procollagen-n-proteinase was increased in SHR and had the highest expression in the JMC. The mRNA for MMP-2 and MMP-9 showed increased expression in SHR, but not specifically in the JMC. Protein analysis showed increased expression for MMP-2 in SHR and in the JMC. MMP-9 protein was lower in SHR. TIMP-1 was increased in SHR at both mRNA and protein level and more so in the JMC. The mRNA and protein analysis of TIMP-2 showed small differences between SHR and WKY.
Conclusion. An imbalance of collagen metabolism featuring increased synthesis and inhibition of breakdown favours renal interstitial fibrosis in SHR.
Keywords: hypertension; interstitial fibrosis; MMP; procollagen peptidase; TIMP
Received for publication: 14. 4.07
Accepted in revised form: 12. 9.07