Absence of gelatinase (MMP-9) or collagenase (MMP-13) attenuates adriamycin-induced albuminuria and glomerulosclerosis.
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.
Sakamaki
Yusuke
Y
Department of Internal Medicine, Keio University, Tokyo, Japan.
Sasamura
Hiroyuki
H
Hayashi
Kaori
K
Ishiguro
Kimiko
K
Takaishi
Hironari
H
Okada
Yasunori
Y
D'Armiento
Jeanine M
JM
Saruta
Takao
T
Itoh
Hiroshi
H
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
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