A novel inhibitor of tumor necrosis factor-alpha converting enzyme ameliorates polycystic kidney disease

Background. Transforming growth factor-alpha (TGF-alpha) expression is abno rmal 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 autos omal-recessive kidney disease (ARPKD). In the present Study. kidney TGF-a e xpression 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 (1H) and Western analysis were performed on k idneys from cystic bpk mice and noncystic littermates at postnatal days 7. 14, and 21. Bpk mice and normal controls were treated with WTACE2. a compet itive 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 proxi mal tubules (PT) at postnatal day 7 and collecting tubules (CT) by day 21. A parallel increase in kidney TGF-alpha expression was demonstrated by West ern analysis. Treatment of cystic bpk mice with WTACE2 resulted in a 43% re duction in kidney weight to body weight ratio (11.2 vs. 19.7%). improved cy stic 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 marine ARPKD and demonstrate a ri, that inhibition of T GF-alpha secretion has therapeutic tial in PKI).