TY - JOUR
T1 - MiR-17~92 miRNA cluster promotes kidney cyst growth in polycystic kidney disease
AU - Patel, Vishal
AU - Williams, Darren
AU - Hajarnis, Sachin
AU - Hunter, Ryan
AU - Pontoglio, Marco
AU - Somlo, Stefan
AU - Igarashi, Peter
PY - 2013/6/25
Y1 - 2013/6/25
N2 - 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-17~92, an oncogenic miRNA cluster, is up-regulated in mouse models of PKD. Kidney-specific transgenic overexpression of miR-17~92 produces kidney cysts in mice. Conversely, kidney-specific inactivation of miR-17~92 in a mouse model of PKD retards kidney cyst growth, improves renal function, and prolongs survival. miR- 17~92 may mediate these effects by promoting proliferation and through posttranscriptional repression of PKD genes Pkd1, Pkd2, and hepatocyte nuclear factor-1β. These studies demonstrate a pathogenic role of miRNAs in mouse models of PKD and identify miR- 17~92 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.
AB - 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-17~92, an oncogenic miRNA cluster, is up-regulated in mouse models of PKD. Kidney-specific transgenic overexpression of miR-17~92 produces kidney cysts in mice. Conversely, kidney-specific inactivation of miR-17~92 in a mouse model of PKD retards kidney cyst growth, improves renal function, and prolongs survival. miR- 17~92 may mediate these effects by promoting proliferation and through posttranscriptional repression of PKD genes Pkd1, Pkd2, and hepatocyte nuclear factor-1β. These studies demonstrate a pathogenic role of miRNAs in mouse models of PKD and identify miR- 17~92 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.
KW - Autosomal dominant polycystic kidney disease
KW - Cilia
KW - Kinesin family member 3A
UR - http://www.scopus.com/inward/record.url?scp=84879526558&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84879526558&partnerID=8YFLogxK
U2 - 10.1073/pnas.1301693110
DO - 10.1073/pnas.1301693110
M3 - Article
C2 - 23759744
AN - SCOPUS:84879526558
SN - 0027-8424
VL - 110
SP - 10765
EP - 10770
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 26
ER -