Increased expression of MMP-2, MMP-9 (type IV collagenases/gelatinases), and MT1-MMP in canine X-linked Alport syndrome (XLAS)

Velidi H. Rao, George E. Lees, Clifford E. Kashtan, Ryochi Nemori, Rakesh K. Singh, Daniel T. Meehan, Kathyrn Rodgers, Brian R. Berridge, Gautam Bhattacharya, Dominic Cosgrove

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Background: Alport syndrome is a group of genetic disorders resulting from mutations in either the α3(IV), α4(IV) or α5(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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)1736-1748
Number of pages13
JournalKidney international
Volume63
Issue number5
DOIs
StatePublished - May 1 2003

Bibliographical note

Funding Information:
We thank Ms. Nicole Pearsall and Q. Kong for their help in preparing the histograms and statistical analysis, and Rene Rodgers for sequence analysis. We also thank John (Skip) Kennedy for help in figure preparation. This work is supported in part by NIH R01 DK55000 to D.C., NIH R01 DK57676 to C.E.K., and the tobacco settlement fund from the State of Nebraska.

Keywords

  • Alport syndrome
  • Fibrosis
  • Matrix metalloproteinase

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