期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 26, 页码 10765-10770出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1301693110
关键词
cilia; kinesin family member 3A; autosomal dominant polycystic kidney disease
资金
- University of Texas (UT) Southwestern O'Brien Kidney Research Core Center [P30DK079328]
- National Institute of Diabetes and Digestive and Kidney Diseases [K08DK084311, RC1DK086887, R37DK042921, R01DK54053]
- Pilot and Feasibility grant from the UT Southwestern O'Brien Kidney Research Core Center
- Fondation pour la recherche medicale (equipe FRM)
- European Community [241955]
- Agence Nationale pour le Recherche
Polycystic kidney disease (PKD), the most common genetic cause of chronic kidney failure, is characterized by the presence of numerous, progressively enlarging fluid-filled cysts in the renal parenchyma. The cysts arise from renal tubules and are lined by abnormally functioning and hyperproliferative epithelial cells. Despite recent progress, no Food and Drug Administration-approved therapy is available to retard cyst growth. MicroRNAs (miRNAs) are short noncoding RNAs that inhibit posttranscriptional gene expression. Dysregulated miRNA expression is observed in PKD, but whether miRNAs are directly involved in kidney cyst formation and growth is not known. Here, we show that miR-17 similar to 92, an oncogenic miRNA cluster, is up-regulated in mouse models of PKD. Kidney-specific transgenic overexpression of miR-17 similar to 92 produces kidney cysts in mice. Conversely, kidney-specific inactivation of miR-17 similar to 92 in a mouse model of PKD retards kidney cyst growth, improves renal function, and prolongs survival. miR-17 similar to 92 may mediate these effects by promoting proliferation and through posttranscriptional repression of PKD genes Pkd1, Pkd2, and hepatocyte nuclear factor-1 beta. These studies demonstrate a pathogenic role of miRNAs in mouse models of PKD and identify miR-17 similar to 92 as a therapeutic target in PKD. Our results also provide a unique hypothesis for disease progression in PKD involving miRNAs and regulation of PKD gene dosage.
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