Faculty Collaboration Database

A novel inhibitor of tumor necrosis factor-alpha converting enzyme ameliorates polycystic kidney disease. Kidney Int 2001 Oct;60(4):1240-8

Date

09/29/2001

Pubmed ID

11576338

DOI

10.1046/j.1523-1755.2001.00963.x

Scopus ID

2-s2.0-0034799491 (requires institutional sign-in at Scopus site)   63 Citations

Abstract

BACKGROUND: Transforming growth factor-alpha (TGF-alpha) expression is abnormal in polycystic kidney disease. We previously demonstrated that blockade of the epidermal growth factor receptor (EGFR), the receptor for TGF-alpha, significantly slowed disease progression in the bpk murine model of autosomal-recessive kidney disease (ARPKD). In the present study, kidney TGF-alpha expression in this model is characterized, and the therapeutic potential of inhibiting TGF-alpha in ARPKD is examined using a novel inhibitor of tumor necrosis factor-alpha converting enzyme (TACE), the metalloproteinase that cleaves membrane-bound TGF-alpha to release the secreted ligand.

METHODS: Immunohistochemistry (IH) and Western analysis were performed on kidneys from cystic bpk mice and noncystic littermates at postnatal days 7, 14, and 21. Bpk mice and normal controls were treated with WTACE2, a competitive inhibitor of TACE, from day 7 until day 21, and the effects on kidney histology and renal function were assessed.

RESULTS: Increased TGF-alpha expression by IH was demonstrated in the proximal tubules (PT) at postnatal day 7 and collecting tubules (CT) by day 21. A parallel increase in kidney TGF-alpha expression was demonstrated by Western analysis. Treatment of cystic bpk mice with WTACE2 resulted in a 43% reduction in kidney weight to body weight ratio (11.2 vs. 19.7%), improved cystic index (3.2 vs. 4.8), reduced cystic CT to PT ratio (1.2 vs. 8), and a greater than 30% reduction in BUN and serum creatinine.

CONCLUSIONS: These findings support the pathophysiological role of the TGF-alpha/EGFR axis in murine ARPKD and demonstrate that inhibition of TGF-alpha secretion has therapeutic potential in PKD.

Author List

Dell KM, Nemo R, Sweeney WE Jr, Levin JI, Frost P, Avner ED

Author

Ellis D. Avner MD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

ADAM Proteins
ADAM17 Protein
Aging
Animals
Animals, Newborn
Hydroxamic Acids
Immunohistochemistry
Kidney
Metalloendopeptidases
Mice
Mice, Inbred Strains
Polycystic Kidney, Autosomal Recessive
Sulfonamides
Transforming Growth Factor alpha