title: MicroRNA-21 Aggravates Cyst Growth in a Model of Polycystic Kidney Disease.
abstract: 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.
authors.affiliation: Department of Internal Medicine and.
authors.forename: Ronak
authors.initials: R
authors.lastname: Lakhia
authors.affiliation: Department of Internal Medicine and.
authors.forename: Sachin
authors.initials: S
authors.lastname: Hajarnis
authors.affiliation: Department of Internal Medicine and.
authors.forename: Darren
authors.initials: D
authors.lastname: Williams
authors.affiliation: Department of Internal Medicine, University of Minnesota Medical School, Minneapolis, Minnesota;
authors.forename: Karam
authors.initials: K
authors.lastname: Aboudehen
authors.affiliation: Department of Internal Medicine and.
authors.forename: Matanel
authors.initials: M
authors.lastname: Yheskel
authors.affiliation: McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas;
authors.forename: Chao
authors.initials: C
authors.lastname: Xing
authors.affiliation: Department of Oncology, St. Jude's Children's Research Hospital, Memphis, Tennessee;
authors.forename: Mark E
authors.initials: ME
authors.lastname: Hatley
authors.affiliation: Departments of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota; and.
authors.forename: Vicente E
authors.initials: VE
authors.lastname: Torres
authors.affiliation: Department of Internal Medicine and the Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Darren P
authors.initials: DP
authors.lastname: Wallace
authors.affiliation: Department of Internal Medicine and Vishald.patel@utsouthwestern.edu.
authors.forename: Vishal
authors.initials: V
authors.lastname: Patel
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D016891:Polycystic Kidney, Autosomal Dominant / Q000209:etiology* / Q000473:pathology*; D012720:Severity of Illness Index
chemical_list: D035683:MicroRNAs; C531950:MIRN21 microRNA, mouse
keywords: cell death; miR-21; microRNAs; polycystic kidney disease