Increased expression of MMP-2, MMP-9 (type IV collagenases/gelatinases), and MT1-MMP in canine X-linked Alport syndrome (XLAS).
BACKGROUND
Alport syndrome is a group of genetic disorders resulting from mutations in either the alpha3(IV), alpha4(IV) or alpha5(IV) collagen chains. The disease is characterized by a progressive glomerulonephritis, usually associated with a high-frequency specific sensorineural hearing loss, dot and fleck retinopathy, and lens abnormalities. Dogs with naturally occurring genetic disorders of basement membrane collagen (type IV) may serve as animal models of Alport syndrome. In this study, a well-characterized naturally occurring canine model was employed to demonstrate a potential role for matrix metalloproteinases (MMPs) in Alport renal disease pathogenesis.


METHODS
Adolescent male dogs that developed renal failure were euthanized and necropsied. Clinicopathologic features of the disease were characterized, and kidneys from normal and Alport dogs were analyzed by gelatin zymography, Western blotting, in situ zymography, immunohistology, and by reverse transcription polymerase chain reaction (RT-PCR) for expression of MMP-2, MMP-9, and membrane type 1-MMP (MT1-MMP).


RESULTS
Affected dogs developed proteinuria and rapidly progressive juvenile-onset chronic renal failure. The activities of MMP-2 and MMP-9 were significantly induced in Alport kidney. In situ zymography confirmed elevated active metalloproteinases in kidney cryosections of affected dogs. The mRNAs encoding MMP-2, MMP-9 and MT1-MMP were also increased in Alport dogs suggesting that elevated expression of MMPs reflects events in the progression of Alport syndrome in dogs.


CONCLUSIONS
Elevated expression of MMP-2, MMP-9, and MT1-MMP is observed in fibrotic renal cortex from X-linked Alport syndrome dogs. These findings suggest that MMPs may play an important role in matrix accumulation associated with progressive renal scarring in this model.
Rao
Velidi H
VH
Boys Town National Research Hospital, Omaha, Nebraska 68131, USA.
Lees
George E
GE
Kashtan
Clifford E
CE
Nemori
Ryochi
R
Singh
Rakesh K
RK
Meehan
Daniel T
DT
Rodgers
Kathyrn
K
Berridge
Brian R
BR
Bhattacharya
Gautam
G
Cosgrove
Dominic
D
D000818:Animals; D004285:Dogs; D005355:Fibrosis; D005780:Gelatin; D015971:Gene Expression Regulation, Enzymologic; D007672:Kidney Cortex / Q000201:enzymology / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D009394:Nephritis, Hereditary / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D012333:RNA, Messenger / Q000032:analysis; D014960:X Chromosome
D012333:RNA, Messenger; D005780:Gelatin; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9