TWEAK Signaling Pathway Blockade Slows Cyst Growth and Disease Progression in Autosomal Dominant Polycystic Kidney Disease
Adrián Cordido, Laura Núñez-González, Julio M. Martínez‐Moreno, Olaya Lamas-González, Laura Rodríguez-Osorio, María Vanessa Pérez-Gómez, Diego Martín‐Sánchez, Patricia Outeda, Marco Chiaravalli, Terry Watnick, Alessandra Boletta, Cándido Díaz, Ãngel Carracedo, Ana B. Sanz, Alberto Ortíz, Miguel A. García-González
Abstract
Significance Statement In autosomal dominant polycystic kidney disease (ADPKD), interstitial inflammation promotes cyst progression. TWEAK is a TNF superfamily cytokine that regulates inflammatory responses, and its receptor, Fn14, is expressed in nephron epithelium. This paper describes TWEAK’s role in ADPKD and its potential as a therapeutic target. The Fn14/TWEAK axis is upregulated in human and mouse polycystic kidneys, and TWEAK administration in mice accelerates cyst progression, whereas anti-TWEAK treatment slows cyst growth, improving kidney function and survival. Anti-TWEAK antibodies restore several ADPKD-related pathways, such as proliferation and NF- κ B; slightly reduces fibrosis and apoptosis; and indirectly decreases macrophage recruitment. These findings identify the TWEAK signaling pathway as a new disease mechanism in ADPKD and a new possible therapeutic approach. Background In autosomal dominant polycystic kidney disease (ADPKD), cyst development and enlargement lead to ESKD. Macrophage recruitment and interstitial inflammation promote cyst growth. TWEAK is a TNF superfamily (TNFSF) cytokine that regulates inflammatory responses, cell proliferation, and cell death, and its receptor Fn14 (TNFRSF12a) is expressed in macrophage and nephron epithelia. Methods To evaluate the role of the TWEAK signaling pathway in cystic disease, we evaluated Fn14 expression in human and in an orthologous murine model of ADPKD. We also explored the cystic response to TWEAK signaling pathway activation and inhibition by peritoneal injection. Results Meta-analysis of published animal-model data of cystic disease reveals mRNA upregulation of several components of the TWEAK signaling pathway. We also observed that TWEAK and Fn14 were overexpressed in mouse ADPKD kidney cysts, and TWEAK was significantly high in urine and cystic fluid from patients with ADPKD. TWEAK administration induced cystogenesis and increased cystic growth, worsening the phenotype in a murine ADPKD model. Anti-TWEAK antibodies significantly slowed the progression of ADPKD, preserved renal function, and improved survival. Furthermore, the anti-TWEAK cystogenesis reduction is related to decreased cell proliferation–related MAPK signaling, decreased NF- κ B pathway activation, a slight reduction of fibrosis and apoptosis, and an indirect decrease in macrophage recruitment. Conclusions This study identifies the TWEAK signaling pathway as a new disease mechanism involved in cystogenesis and cystic growth and may lead to a new therapeutic approach in ADPKD.