Loss of TIMP3 enhances interstitial nephritis and fibrosis.
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 TNFalpha, demonstrated by significantly higher TACE activity and greater soluble TNFalpha levels by 3 d after UUO. The additional deletion of TNFalpha markedly reduced inflammation, apoptosis, and induction of a number of MMPs. Moreover, inhibition of MMPs in TIMP3-/-/TNFalpha-/- 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.
Kassiri
Zamaneh
Z
Department of Physiology, Cardiovascular Research Group, Room 474, Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, T6G 2S2 Canada. z.kassiri@ualberta.ca
Oudit
Gavin Y
GY
Kandalam
Vijay
V
Awad
Ahmed
A
Wang
Xiuhua
X
Ziou
Xiuhua
X
Maeda
Nobuyo
N
Herzenberg
Andrew M
AM
Scholey
James W
JW
D000368:Aged; D000375:Aging / Q000502:physiology; D000818:Animals; D017209:Apoptosis; D016022:Case-Control Studies; D003928:Diabetic Nephropathies / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D006084:Graft Rejection / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009395:Nephritis, Interstitial / Q000378:metabolism*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014517:Ureteral Obstruction
D019717:Tissue Inhibitor of Metalloproteinase-3; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases