miR-17∼92 miRNA cluster promotes kidney cyst growth in polycystic kidney disease

Abstract

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.cilia | kinesin family member 3A | autosomal dominant polycystic kidney disease P olycystic kidney disease (PKD) is among the most common monogenic human diseases (1, 2). PKD is characterized by the presence of numerous fluid-filled cysts in the renal parenchyma. The cysts arise from renal tubules and are lined by abnormally functioning epithelial cells. The cyst epithelial cells secrete excessive fluid and display high rates of proliferation, which results in cyst expansion. The expanding cysts compress the surrounding normal nephrons, which cause renal failure. Based on the mode of inheritance, PKD is classified into autosomal dominant PKD (ADPKD) and autosomal recessive PKD (ARPKD). ADPKD is caused by mutations of PKD1 or PKD2, which encode polycystin-1 and polycystin-2, respectively. ARPKD is caused by mutations of polycystic kidney and hepatic disease 1 (PKHD1) which encodes fibrocystin (1, 3). Polycystin-1, polycystin-2, and fibrocystin localize to the primary cilium, a sensory organelle present on the apical surface of most cells in the body. Abnormalities of the primary cilium are linked to the pathogenesis of many forms of cystic kidney diseases, including PKD (1, 4, 5). Despite recent advances, no Food and Drug Administration-approved therapy is available for PKD patients.MicroRNAs (miRNAs) are noncoding RNAs that constitute the endogenous RNA interference pathway. miRNAs are transcribed as primary miRNAs (pri-miRNAs), which are sequentially processed by the enzymes Drosha and Dicer to produce mature miRNAs (6). Watson-Crick base pairing between nucleotides 2-8 (seed sequence) at the 5′ end of the matur...

c-Myc Signalling in the Genetic Mechanism of Polycystic Kidney Disease

“…Transgenic mice overexpressing miR-17~92 developed renal tubular and glomerular cysts. Conversely, inactivation of miR-17~92 caused delay of cystic progression in non-orthologous mouse models (96).…”

MicroRNA-21 Aggravates Cyst Growth in a Model of Polycystic Kidney Disease

“…9 Quantitative realtime PCR (qPCR) validation of this dataset revealed that miR-21 was among the most robustly upregulated miRs in 28-day-old Kif3a mutant kidneys compared with control kidneys ( Figure 1A). Therefore, we decided to study the role of miR-21 in greater detail.…”

“…Cyst index and cyst number calculations were performed using ImageJ analysis software as previously described. 9 Serum creatinine was measured using capillary electrophoresis; BUN, aspartate aminotransferase, and alanine aminotransferase were measured using the Vitros 250 Analyzer. Four-week-old Pkd2 WS25/2 mice were treated with either mozavaptan (OPC31260) or vehicle for 3 months; 0.1% OPC31260 was added to ground rodent chow (LaDiet 5053).…”

“…8 miRs have been implicated in normal kidney development and the pathogenesis of many kidney diseases, including polycystic kidney disease (PKD). [9][10][11][12] We have previously shown that the miR-17~92 cluster promotes kidney cyst growth. 9 However, whether other miRs also regulate PKD pathogenesis is not known.…”

“…[9][10][11][12] We have previously shown that the miR-17~92 cluster promotes kidney cyst growth. 9 However, whether other miRs also regulate PKD pathogenesis is not known. The goal of this study was to determine whether miR-21, an oncogenic miR, 13,14 modulates cyst growth in ADPKD.…”