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

Abstract

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.

Loss of TIMP3 Enhances Interstitial Nephritis and Fibrosis

“…Although we have shown a clear role of TNF␣ in mediating the renal injury, we cannot rule out a contributing role of other renal injury-inducing agonists such as TGF␣. 32,51 Collectively, our data reveal a mechanistic dual role of TIMP3 in kidney disease, as a negative regulator of TACE/ADAM-17 and MMP axes. The pathophysiological importance of TIMP3 is fur- Ϫ/Ϫ kidneys at 3 d post-UUO, suggesting enhanced processing of TNF␣ protein by TACE early after disease in these mice compared with WT (n ϭ 5).…”

Transforming Growth Factor Alpha (TGF-α) and Other Targets of Tumor Necrosis Factor-Alpha Converting Enzyme (TACE) in Murine Polycystic Kidney Disease

“…Severity of cystic kidney disease was qualitatively assessed by staining serial sections with biotinylated lectins specific for collecting tubule (CT) [Dolichos biflorus agglutinin (DBA)] and proximal tubule (PT) [Lotus tetragonolobus (LTA)], and counterstained with hematoxylin, as described (2). The ratio of cystic CT to PT was also assessed, as described (2).…”

“…Numerous studies have implicated the EGFR and its ligand, TGF-␣, in the pathogenesis of this abnormal cell proliferation. EGFR and TGF-␣ are abnormally expressed in murine and human PKD (2)(3)(4). Transgenic mice that overexpress TGF-␣ develop cystic kidneys (5).…”

“…Treatment with novel inhibitors of EGFR tyrosine kinase significantly attenuated the severity of cystic kidney disease in the bpk mouse model of ARPKD and the Han-SPRD rat model of autosomal dominant PKD (ADPKD) (7,8). Treatment of cystic bpk mice with a novel inhibitor of TACE, the metalloproteinase that mediates TGF-␣ ectodomain shedding, significantly reduced the severity of cystic kidney disease (2). Furthermore, when compared with single higher dose EGFR inhibitor therapy, combination therapy with a TACE inhibitor and a decreased dose of an EGFR inhibitor was as effective (9), suggesting a synergistic effect of the two.…”

Novel Therapies for Polycystic Kidney Disease

“…It appears that TNF-α disrupts polycystin 2 through increased expression of FIP2, a scaffolding protein that binds polycystin 2 in murine PKD2+/-kidneys [21]. Treating pkd2+/-embryonic kidneys with TNF-α stimulated cyst formation and inhibition of TNF-α was effective at preventing cystic disease in postnatal pkd2+/-mice [22,23]. TNF-α administration has also been associated with significant amelioration of renal cystic pathology in a non-orthologous murine model of ARPKD [24].…”