RESUMO
Autosomal-dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, primarily caused by germline mutation of PKD1 or PKD2, leading to end-stage renal disease. The Hippo signaling pathway regulates organ growth and cell proliferation. Herein, we demonstrate the regulatory mechanism of cystogenesis in ADPKD by transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo signaling effector. TAZ was highly expressed around the renal cyst-lining epithelial cells of Pkd1-deficient mice. Loss of Taz in Pkd1-deficient mice reduced cyst formation. In wild type, TAZ interacted with PKD1, which inactivated ß-catenin. In contrast, in PKD1-deficient cells, TAZ interacted with AXIN1, thus increasing ß-catenin activity. Interaction of TAZ with AXIN1 in PKD1-deficient cells resulted in nuclear accumulation of TAZ together with ß-catenin, which up-regulated c-MYC expression. Our findings suggest that the PKD1-TAZ-Wnt-ß-catenin-c-MYC signaling axis plays a critical role in cystogenesis and might be a potential therapeutic target against ADPKD.
Assuntos
Doenças Renais Policísticas/genética , Doenças Renais Policísticas/metabolismo , Rim Policístico Autossômico Dominante/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transativadores/metabolismo , Via de Sinalização Wnt/fisiologia , beta Catenina/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Proteína Axina , Proliferação de Células , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Humanos , Rim/metabolismo , Rim/patologia , Camundongos , Camundongos Knockout , Doenças Renais Policísticas/patologia , Rim Policístico Autossômico Dominante/genética , Rim Policístico Autossômico Dominante/patologia , Proteína Quinase C/deficiência , Proteína Quinase C/genética , Canais de Cátion TRPP/genética , TranscriptomaRESUMO
BACKGROUND: Polycystic kidney disease (PKD) involves renal cysts arising from proliferating tubular cells. Autophagy has been recently suggested as a potential therapeutic target in PKD, and mammalian target of rapamycin (mTOR) is a key negative regulator of autophagy. However, the effect of autophagy regulation on cystogenesis has not been elucidated in PKD mice. METHODS: Clinical validation was performed using GEO datasets and autosomal dominant polycystic kidney disease (ADPKD) patient samples. Newly established PKD and LC3 transgenic mice were used for in vivo verifications, and additional tests were performed in vitro and in vivo using multiple autophagy drugs. FINDINGS: Neither autophagy stimulation nor LC3 overexpression alleviated PKD. Furthermore, we observed the inhibitory effect of an autophagy inhibitor on cysts, indicating its possible therapeutic use in a specific group of patients with ADPKD. INTERPRETATION: Our findings provide a novel insight into the pathogenesis related to autophagy in PKD, suggesting that drugs related to autophagy regulation should be considered with caution for treating PKD. FUNDING SOURCES: This work was supported by grants from the Bio & Medical Technology Development Program; the Collaborative Genome Program for Fostering New Post-Genome Industry of the NRF; the Basic Science Program.
