Abstract
Tissue inhibitor of metalloproteinase-3 (Timp-3), an inhibitor of matrix-degrading enzymes, is an important molecule for maintenance of the extracellular matrix. In this study, we generated Timp-3−deficient mice and used them to examine the effect of Timp-3-deficiency on blood pressure and to investigate the role of Timp-3 in the kidney following unilateral ureteral obstruction. The blood pressure and heart rate of Timp-3−deficient mice were not significantly different from those of wild-type mice. On the other hand, the obstructed kidneys of Timp-3−deficient mice developed more severe hydronephrosis than those of wild-type animals. Matrix metalloproteinase activities assessed by in situ zymography and transforming growth factor-β expression were elevated in Timp-3−deficient mice. The renal tissues were thinner and the ratio of renal medulla to cortex was significantly lower in the obstructed Timp-3−deficient kidneys. These findings indicate that Timp-3-deficiency does not substantially affect the blood pressure in mice, and that Timp-3 plays an important role in the maintenance of renal macrostructure after unilateral ureteral obstruction.
Similar content being viewed by others
Article PDF
References
Diamond JA, Phillips RA : Hypertensive heart disease. Hypertens Res 2005; 28: 191–202.
Firestein GS : Evolving concepts of rheumatoid arthritis. Nature 2003; 423: 356–361.
Tsunemi K, Takai S, Miyazaki M, et al: Possible roles of angiotensin II–forming enzymes, angiotensin converting enzyme and chymase-like enzyme, in the human aneurysmal aorta. Hypertens Res 2002; 25: 817–822.
Iwashima Y, Horio T, Kuroda S, Takishita S, Kawano Y : Influence of plasma aldosterone on left ventricular geometry and diastolic function in treated essential hypertension. Hypertens Res 2002; 25: 49–56.
Pavloff N, Staskus PW, Kishnani NS, Hawkes SP : A new inhibitor of metalloproteinases from chicken: ChIMP-3. A third member of the TIMP family. J Biol Chem 1992; 267: 17321–17326.
Leco KJ, Khokha R, Pavloff N, Hawkes SP, Edwards DR : Tissue inhibitor of metalloproteinases-3 (TIMP-3) is an extracellular matrix–associated protein with a distinctive pattern of expression in mouse cells and tissues. J Biol Chem 1994; 269: 9352–9360.
Fedak PW, Verma S, Weisel RD, Li RK : Cardiac remodeling and failure from molecules to man (Part II). Cardiovasc Pathol 2005; 14: 49–60.
Amour A, Slocombe PM, Murphy G, et al: TNF-alpha converting enzyme (TACE) is inhibited by TIMP-3. FEBS Lett 1998; 435: 39–44.
Bian J, Wang Y, Sun Y, et al: Suppression of in vivo tumor growth and induction of suspension cell death by tissue inhibitor of metalloproteinases (TIMP)-3. Carcinogenesis 1996; 17: 1805–1811.
Cruz-Munoz W, Kim I, Khokha R : TIMP-3 deficiency in the host, but not in the tumor, enhances tumor growth and angiogenesis. Oncogene 2006; 25: 650–655.
Baker AH, George SJ, Zaltsman AB, Murphy G, Newby AC : Inhibition of invasion and induction of apoptotic cell death of cancer cell lines by overexpression of TIMP-3. Br J Cancer 1999; 79: 1347–1355.
Baker AH, Zaltsman AB, George SJ, Newby AC : Divergent effects of tissue inhibitor of metalloproteinase-1, -2, or -3 overexpression on rat vascular smooth muscle cell invasion, proliferation, and death in vitro. TIMP-3 promotes apoptosis. J Clin Invest 1998; 101: 1478–1487.
Bond M, Murphy G, Baker AH, et al: Localization of the death domain of tissue inhibitor of metalloproteinase-3 to the N terminus. Metalloproteinase inhibition is associated with proapoptotic activity. J Biol Chem 2000; 275: 41358–41363.
Qi JH, Ebrahem Q, Anand-Apte B, et al: A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat Med 2003; 9: 407–415.
Weber BH, Vogt G, Pruett RC, Stohr H, Felbor U : Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby's fundus dystrophy. Nat Genet 1994; 8: 352–356.
Pulido J, Sanders D, Winters JL, Klingel R : Clinical outcomes and mechanism of action for rheopheresis treatment of age-related macular degeneration (AMD). J Clin Apher 2005; 20: 185–194.
Klahr S, Morrissey J : Obstructive nephropathy and renal fibrosis. Am J Physiol Renal Physiol 2002; 283: F861–F875.
Bascands JL, Schanstra JP : Obstructive nephropathy: insights from genetically engineered animals. Kidney Int 2005; 68: 925–937.
Saito K, Ishizaka N, Nagai R, et al: Role of aberrant iron homeostasis in the upregulation of transforming growth factor-β1 in the kidney of angiotensin II–induced hypertensive rats. Hypertens Res 2004; 27: 599–607.
Oda T, Jung YO, Eddy AA, et al: PAI-1 deficiency attenuates the fibrogenic response to ureteral obstruction. Kidney Int 2001; 60: 587–596.
Engelmyer E, van Goor H, Edwards DR, Diamond JR : Differential mRNA expression of renal cortical tissue inhibitor of metalloproteinase-1, -2, and -3 in experimental hydronephrosis. J Am Soc Nephrol 1995; 5: 1675–1683.
Kim H, Oda T, Lopez-Guisa J, Eddy AA, et al: TIMP-1 deficiency does not attenuate interstitial fibrosis in obstructive nephropathy. J Am Soc Nephrol 2001; 12: 736–748.
Apte SS, Olsen BR, Murphy G : The gene structure of tissue inhibitor of metalloproteinases (TIMP)-3 and its inhibitory activities define the distinct TIMP gene family. J Biol Chem 1996; 271: 2874.
Bronson SK, Plaehn EG, Kluckman KD, Hagaman JR, Maeda N, Smithies O : Single-copy transgenic mice with chosen-site integration. Proc Natl Acad Sci U S A 1996; 93: 9067–9072.
Nagatoya K, Moriyama T, Hori M, et al: Y-27632 prevents tubulointerstitial fibrosis in mouse kidneys with unilateral ureteral obstruction. Kidney Int 2002; 61: 1684–1695.
Mizuno S, Matsumoto K, Nakamura T : Hepatocyte growth factor suppresses interstitial fibrosis in a mouse model of obstructive nephropathy. Kidney Int 2001; 59: 1304–1314.
Moriyama T, Kawada N, Hori M, et al: Up-regulation of HSP47 in the mouse kidneys with unilateral ureteral obstruction. Kidney Int 1998; 54: 110–119.
Mizuno S, Matsumoto K, Kurosawa T, Mizuno-Horikawa Y, Nakamura T : Reciprocal balance of hepatocyte growth factor and transforming growth factor-beta 1 in renal fibrosis in mice. Kidney Int 2000; 57: 937–948.
Muramatsu M, Takai S, Miyazaki M : Detections of matrix metalloproteinases activities and localization by film in situ zymography (FIZ). Nippon Yakurigaku Zasshi 2003; 121: 113–118 ( in Japanese).
Lan HY, Mu W, Morishita R, et al: Inhibition of renal fibrosis by gene transfer of inducible Smad7 using ultrasound-microbubble system in rat UUO model. J Am Soc Nephrol 2003; 14: 1535–1548.
Kuncio GS, Neilson EG, Haverty T : Mechanisms of tubulointerstitial fibrosis. Kidney Int 1991; 39: 550–556.
Leco KJ, Waterhouse P, Khokha R, et al: Spontaneous air space enlargement in the lungs of mice lacking tissue inhibitor of metalloproteinases-3 (TIMP-3). J Clin Invest 2001; 108: 817–829.
Fedak PW, Smookler DS, Khokha R, et al: TIMP-3 deficiency leads to dilated cardiomyopathy. Circulation 2004; 110: 2401–2409.
Ishimitsu T, Kobayashi T, Matsuoka H, et al: Protective Effects of an angiotensin II receptor blocker and a long-acting calcium channel blocker against cardiovascular organ injuries in hypertensive patients. Hypertens Res 2005; 28: 351–359.
Wu I, Moses MA : Cloning and expression of the cDNA encoding rat tissue inhibitor of metalloproteinase-3 (TIMP-3). Gene 1996; 168: 243–246.
Asai M, Monkawa T, Saruta T, et al: Spironolactone in combination with cilazapril ameliorates proteinuria and renal interstitial fibrosis in rats with anti–Thy-1 irreversible nephritis. Hypertens Res 2004; 27: 971–978.
Sato A, Saruta T : Aldosterone-induced organ damage: plasma aldosterone level and inappropriate salt status. Hypertens Res 2004; 27: 303–310.
Yokoi H, Mukoyama M, Nagae T, et al: Reduction in connective tissue growth factor by antisense treatment ameliorates renal tubulointerstitial fibrosis. J Am Soc Nephrol 2004; 15: 1430–1440.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kawamoto, H., Yasuda, O., Suzuki, T. et al. Tissue Inhibitor of Metalloproteinase-3 Plays Important Roles in the Kidney Following Unilateral Ureteral Obstruction. Hypertens Res 29, 285–294 (2006). https://doi.org/10.1291/hypres.29.285
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1291/hypres.29.285
Keywords
This article is cited by
-
TIMP3 involvement and potentiality in the diagnosis, prognosis and treatment of diabetic nephropathy
Acta Diabetologica (2021)
-
Proteomic and metabolomic characterization of streptozotocin-induced diabetic nephropathy in TIMP3-deficient mice
Acta Diabetologica (2018)
-
Regulation of TIMP3 in diabetic nephropathy: a role for microRNAs
Acta Diabetologica (2013)
-
Timp-3 deficiency impairs cognitive function in mice
Laboratory Investigation (2009)