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Loss of TIMP3 Enhances Interstitial Nephritis and Fibrosis

Zamaneh Kassiri^*,, Gavin Y. Oudit^,, Vijay Kandalam^*, Ahmed Awad^*, Xiuhua Wang^*, Xiuhua Ziou, Nobuyo Maeda^||, Andrew M. Herzenberg^¶ and James W. Scholey

^* Department of Physiology, Cardiovascular Research Group, University of Alberta; Division of Cardiology, Department of Medicine, University of Alberta; Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada; Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; ^|| University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; ^¶ Department of Pathology, University of Toronto, Toronto, Ontario, Canada

Correspondence: Zamaneh Kassiri, MSc, PhD, Department of Physiology, Room 474, Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, T6G 2S2 Canada. Phone: 780-492-49283; Fax: 780-4492-49753; E-mail: z.kassiri{at}ualberta.ca

Received for publication May 13, 2008. Accepted for publication January 13, 2009.

The balance of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) determines the integrity of the extracellular matrix. TIMP3 is the most highly expressed tissue inhibitor of metalloproteinase (TIMP) in the kidney, but its function in renal disease is incompletely understood. In this study, TIMP3^–/– mice demonstrated an age-dependent chronic tubulointerstitial fibrosis. After unilateral ureteral obstruction (UUO), young TIMP3^–/– mice exhibited increased renal injury (tubular atrophy, cortical and medullary thinning, and vascular damage) compared with wild-type mice. In addition, TIMP3^–/– mice had greater interstitial fibrosis; increased synthesis and deposition of type I collagen; increased activation of fibroblasts; enhanced apoptosis; and greater activation of MMP2, but not MMP9, after UUO. TIMP3 deficiency also led to accelerated processing of TNF, demonstrated by significantly higher TACE activity and greater soluble TNF levels by 3 d after UUO. The additional deletion of TNF markedly reduced inflammation, apoptosis, and induction of a number of MMPs. Moreover, inhibition of MMPs in TIMP3^–/–/TNF^–/– mice further abrogated postobstructive injury and prevented tubulointerestitial fibrosis. In humans, TIMP3 expression increased in the renal arteries and proximal tubules of subjects with diabetic nephropathy or chronic allograft nephropathy. Taken together, these results provide evidence that TIMP3 is an important mediator of kidney injury, and regulating its activity may have therapeutic benefit for patients with kidney disease.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673