MicroRNAs Regulate Renal Tubule Maturation through Modulation of Pkd1

Patel, Vishal; Hajarnis, Sachin; Williams, Darren R.; Hunter, Ryan; Huynh, Donovan; Igarashi, Peter

doi:10.1681/asn.2012030321

Cited by 84 publications

(95 citation statements)

References 31 publications

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“…81 PC1 overexpression is observed in cystic epithelia of ADPKD patients, 96 and its overexpression disrupts tubule formation in renal epithelial cells in mice. 97 In contrast, the downregulation of PC1 induces cystogenesis in mouse models. 98 A major conclusion of these studies is that the dosage of PC1 is important for cystogenesis.…”

Section: Autophagy and Ciliummentioning

confidence: 99%

Autophagy and regulation of cilia function and assembly

et al. 2014

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Motile and primary cilia (PC) are microtubule-based structures located at the cell surface of many cell types. Cilia govern cellular functions ranging from motility to integration of mechanical and chemical signaling from the environment. Recent studies highlight the interplay between cilia and autophagy, a conserved cellular process responsible for intracellular degradation. Signaling from the PC recruits the autophagic machinery to trigger autophagosome formation. Conversely, autophagy regulates ciliogenesis by controlling the levels of ciliary proteins. The cross talk between autophagy and ciliated structures is a novel aspect of cell biology with major implications in development, physiology and human pathologies related to defects in cilium function. Cell Death and Differentiation (2015) 22, 389-397; doi:10.1038/cdd.2014.171; published online 31 October 2014 FactsAutophagy is a degradative and recycling mechanism that allows cells to adapt to stress situations including nutrient deprivation. Primary cilia (PC) and motile cilia (MC) are sensory structures at the cell surface. PC sense nutrient, growth factor and calcium changes in the extracellular environment and also respond to mechanical stress. MC are beating structures that contribute to innate defense in the lung, for example. The PC is a site for the recruitment of autophagy-related (ATG) proteins that mediate autophagosome formation in response to cilium-dependent signaling. In turn, autophagy regulates the biogenesis of cilia by degrading certain proteins involved in cilia formation. Modulation of autophagy represents a new therapeutic opportunity in diseases related to defective cilia function. Open QuestionsHow are ATG proteins transported to the PC? How do ATG proteins recruited to the PC contribute to the biogenesis of phagophores and autophagosomes? Ciliary proteins are degraded by autophagy. How selective is this degradative pathway? Do some of these proteins contain motifs that result in selective engulfment by autophagosomes?What are the determinants that switch the degradation of ciliary proteins between basal and induced autophagy? Is there any specific function for cilium-dependent autophagy in ciliated cells? Do signals that trigger cilium-dependent autophagy depend on the stimuli (chemical, mechanical) or do all stimuli converge to a single signaling pathway upstream of the autophagy machinery? Can modulation of autophagy contribute to the restoration of cilium functions?Receptors, transporters and specialized plasma membrane structures such as cilia constitute the interfaces between the extracellular and intracellular milieu and allow the cells to trigger specific responses to adapt to changes imposed by the environment. Among these adaptive responses, macroautophagy (hereafter referred to as 'autophagy') is a catabolic process conserved in eukaryotic cells by which the cell recycles its own constituents. 1 Autophagy is involved in the adaptation to starvation, cell differentiation and development, the degradation of aberrant structure...

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Section: Autophagy and Ciliummentioning

confidence: 99%

Autophagy and regulation of cilia function and assembly

et al. 2014

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“…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.…”

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

Lakhia¹,

Hajarnis²,

Williams³

et al. 2015

JASN

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Autosomal dominant polycystic kidney disease (ADPKD), one of the most common monogenetic disorders, is characterized by kidney failure caused by bilateral renal cyst growth. MicroRNAs (miRs) have been implicated in numerous diseases, but the role of these noncoding RNAs in ADPKD pathogenesis is still poorly defined. Here, we investigated the role of miR-21, an oncogenic miR, in kidney cyst growth. We found that transcriptional activation of miR-21 is a common feature of murine PKD. Furthermore, compared with renal tubules from kidney samples of normal controls, cysts in kidney samples from patients with ADPKD had increased levels of miR-21. cAMP signaling, a key pathogenic pathway in PKD, transactivated miR-21 promoter in kidney cells and promoted miR-21 expression in cystic kidneys of mice. Genetic deletion of miR-21 attenuated cyst burden, reduced kidney injury, and improved survival of an orthologous model of ADPKD. RNA sequencing analysis and additional in vivo assays showed that miR-21 inhibits apoptosis of cyst epithelial cells, likely through direct repression of its target gene programmed cell death 4. Thus, miR-21 functions downstream of the cAMP pathway and promotes disease progression in experimental PKD. Our results suggest that inhibiting miR-21 is a potential new therapeutic approach to slow cyst growth in PKD.

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“…Aberrant miRNA expression is observed in numerous diseases (7), and correcting miRNA expression has emerged as a novel therapeutic approach (8,9). miRNAs are implicated in normal kidney development (10) and the pathogenesis of several kidney diseases (11).…”

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confidence: 99%

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

Patel¹,

Williams

Hajarnis

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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147

142

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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...

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MicroRNAs Regulate Renal Tubule Maturation through Modulation of Pkd1

Cited by 84 publications

References 31 publications

Autophagy and regulation of cilia function and assembly

Autophagy and regulation of cilia function and assembly

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

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

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