title: Absence of gelatinase (MMP-9) or collagenase (MMP-13) attenuates adriamycin-induced albuminuria and glomerulosclerosis.
abstract: OBJECTIVE
  The role of matrix metalloproteinases (MMPs) in the pathogenesis of glomerular injury appears to be complex. To investigate the role of individual MMPs, we examined the course of Adriamycin-induced albuminuria and glomerulosclerosis in mice lacking either a gelatinase (MMP-9) or a collagenase (MMP-13).
  
  
  METHODS
  Adriamycin was administered to MMP-9 or MMP-13 knockout (KO) mice. Glomerular injury was assessed by the quantification of albuminuria, the glomerular injury score and type IV collagen immunostaining.
  
  
  RESULTS
  Treatment of mice with Adriamycin (18 mg/kg i.v.) resulted in marked albuminuria and glomerulosclerosis reaching a peak at 4-8 weeks. The albuminuria and glomerulosclerosis were significantly (p < 0.05) attenuated in both the MMP-9 KO and MMP-13 KO mice compared to controls. In contrast, treatment of wild-type mice with the broad-spectrum MMP inhibitor doxycycline did not have a beneficial effect on the albuminuria and glomerulosclerosis.
  
  
  CONCLUSIONS
  These results support a role for both gelatinase (MMP-9) and collagenase (MMP-13) in the pathogenesis of glomerular injury in the Adriamycin-induced glomerulosclerosis model. MMP inhibitors with high specificity towards MMP-9 and/or MMP-13 may be potential future candidates to provide more effective therapies to inhibit the development of glomerulosclerosis.
authors.affiliation: Department of Internal Medicine, Keio University, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sakamaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sasamura
authors.forename: Kaori
authors.initials: K
authors.lastname: Hayashi
authors.forename: Kimiko
authors.initials: K
authors.lastname: Ishiguro
authors.forename: Hironari
authors.initials: H
authors.lastname: Takaishi
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Okada
authors.forename: Jeanine M
authors.initials: JM
authors.lastname: D'Armiento
authors.forename: Takao
authors.initials: T
authors.lastname: Saruta
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
mesh_terms: D000419:Albuminuria / Q000139:chemically induced* / Q000188:drug therapy / Q000201:enzymology / Q000517:prevention & control; D000818:Animals; D003199:Computer Systems; D004317:Doxorubicin / Q000633:toxicity*; D004318:Doxycycline / Q000494:pharmacology / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D004790:Enzyme Induction / Q000187:drug effects; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced* / Q000188:drug therapy / Q000201:enzymology / Q000517:prevention & control; D007678:Kidney Glomerulus / Q000201:enzymology; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011897:Random Allocation; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D004317:Doxorubicin; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D004318:Doxycycline