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

A novel inhibitor of tumor necrosis factor-α converting enzyme ameliorates polycystic kidney disease. Background Transforming growth factor-α (TGF-α) expression is abnormal in polycystic kidney disease. We previously demonstrated that blockade of the epidermal growth factor receptor (EGFR), the receptor for TGF-α, significantly slowed disease progression in the bpk murine model of autosomal-recessive kidney disease (ARPKD). In the present study, kidney TGF-α expression in this model is characterized, and the therapeutic potential of inhibiting TGF-α in ARPKD is examined using a novel inhibitor of tumor necrosis factor-α converting enzyme (TACE), the metalloproteinase that cleaves membrane-bound TGF-α 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-α 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-α 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-α/EGFR axis in murine ARPKD and demonstrate that inhibition of TGF-α secretion has therapeutic potential in PKD.