Dysregulation of renal MMP-3 and MMP-7 in canine X-linked Alport syndrome.
Matrix metalloproteinases (MMPs) play an important regulatory role in many biological and pathological processes and their specific role in Alport syndrome (AS) is not yet clearly defined. In this study, the naturally occurring canine X-linked AS was used to demonstrate a potential role for MMP-3 and MMP-7 in Alport renal pathogenesis. Recently, we demonstrated that the expression of MMP-2, MMP-9 and MMP-14 was upregulated in the renal cortex of dogs with a spontaneous form of XLAS. In the present study, we examined necropsy samples of renal cortex from normal and XLAS dogs for MMP-3 and MMP-7 as they have the potential to activate MMP-2 and MMP-9. Immunohistochemical analysis showed strong immunostaining for both MMP-3 and MMP-7 in the interstitial space of XLAS kidneys, while virtually no immunostaining was observed in similar fields from normal dogs. RT-PCR and casein zymography confirmed that both mRNA transcripts and activities of MMP-3 and MMP-7 are elevated in XLAS kidneys. The induction of these MMPs likely contributes to tissue destruction associated with the fibrogenic process, while augmenting the activation of MMP-2 and MMP-9 by MMP-3 and MMP-7 in XLAS. Thus, these data further implicate a role for the MMPs in progressive renal pathogenesis associated with AS.
Rao
Velidi H
VH
Department of Genetics, Boys Town National Research Hospital, Omaha, NE 68131, USA.
Lees
George E
GE
Kashtan
Clifford E
CE
Delimont
Duane C
DC
Singh
Rakesh
R
Meehan
Daniel T
DT
Bhattacharya
Gautam
G
Berridge
Brian R
BR
Cosgrove
Dominic
D
D000818:Animals; D004283:Dog Diseases / Q000201:enzymology* / Q000235:genetics*; D004285:Dogs; D008040:Genetic Linkage; D007668:Kidney / Q000201:enzymology*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009394:Nephritis, Hereditary / Q000235:genetics / Q000662:veterinary*; D014960:X Chromosome
D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3; D020783:Matrix Metalloproteinase 7